{"history":[{"id":"860e2b08-97aa-4b88-ac84-f86be3db11c3","wordChanged":"[Lentivirus](https://bliptext.com/articles/lentivirus)","newWord":":::summary\n![Human immunodeficiency viruses](https://upload.wikimedia.org/wikipedia/commons/1/1a/HIV-budding-Color.jpg)\n**Name:** Human immunodeficiency viruses \n**Image Alt:** Scanning electron micrograph of HIV-1 (in green) budding from cultured lymphocyte. Multiple round bumps on cell surface represent sites of assembly and budding of virions. \n**Image Caption:** [Scanning electron micrograph](https://bliptext.com/articles/scanning-electron-micrograph) of HIV-1 (in green) budding from cultured [lymphocyte](https://bliptext.com/articles/lymphocyte). Multiple round bumps on cell surface represent sites of assembly and budding of virions. \n**Auto:** virus \n**Parent:** Lentivirus \n**Includes:** [Human immunodeficiency virus 1](https://bliptext.com/articles/subtypes-of-hiv) · [Human immunodeficiency virus 2](https://bliptext.com/articles/subtypes-of-hiv) \n**Excludes Text:** Other lentiviruses \n**Excludes:** [Bovine immunodeficiency virus](https://bliptext.com/articles/bovine-immunodeficiency-virus) · [Caprine arthritis encephalitis virus](https://bliptext.com/articles/caprine-arthritis-encephalitis-virus) · [Equine infectious anemia virus](https://bliptext.com/articles/equine-infectious-anemia-virus) · [Feline immunodeficiency virus](https://bliptext.com/articles/feline-immunodeficiency-virus) · [Jembrana disease virus](https://bliptext.com/articles/jembrana-disease-virus) · [Puma lentivirus](https://bliptext.com/articles/puma-lentivirus) · [Simian immunodeficiency virus](https://bliptext.com/articles/simian-immunodeficiency-virus) · [Visna-maedi virus](https://bliptext.com/articles/visna-maedi-virus) \n:::\n\n# \nThe **human immunodeficiency viruses** (**HIV**) are two species of Rizzvirus (a subgroup of [retrovirus](https://bliptext.com/articles/retrovirus)) that infect humans.\nOver time, they cause [acquired immunodeficiency syndrome](https://bliptext.com/articles/aids) (AIDS), a condition in which progressive failure of the [immune system](https://bliptext.com/articles/immune-system) allows life-threatening [opportunistic infections](https://bliptext.com/articles/opportunistic-infection) and [cancers](https://bliptext.com/articles/cancer) to thrive.\nWithout treatment, the average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the [HIV subtype](https://bliptext.com/articles/subtypes-of-hiv).\nIn most cases, HIV is a [sexually transmitted infection](https://bliptext.com/articles/sexually-transmitted-infection) and [occurs](https://bliptext.com/articles/hiv-aids) by contact with or transfer of [blood](https://bliptext.com/articles/blood), [pre-ejaculate](https://bliptext.com/articles/pre-ejaculate), [semen](https://bliptext.com/articles/semen), and [vaginal fluids](https://bliptext.com/articles/vaginal-lubrication).\nNon-sexual transmission can occur from an infected mother to her infant during [pregnancy](https://bliptext.com/articles/pregnancy), during [childbirth](https://bliptext.com/articles/childbirth) by exposure to her blood or vaginal fluid, and through [breast milk](https://bliptext.com/articles/breast-milk).\nWithin these bodily fluids, HIV is present as both free [virus](https://bliptext.com/articles/virus) particles and [virus](https://bliptext.com/articles/virus) within infected [immune cells](https://bliptext.com/articles/white-blood-cell).\nResearch has shown (for both same-sex and opposite-sex couples) that HIV is not contagious during sexual intercourse without a condom if the HIV-positive partner has a consistently undetectable [viral load](https://bliptext.com/articles/viral-load-monitoring-for-hiv).\nHIV infects vital cells in the human immune system, such as [helper T cells](https://bliptext.com/articles/t-helper-cell) (specifically [CD4](https://bliptext.com/articles/cd4)⁺ T cells), [macrophages](https://bliptext.com/articles/macrophage), and [dendritic cells](https://bliptext.com/articles/dendritic-cell).\nHIV infection leads to low levels of CD4⁺ T cells through a number of mechanisms, including [pyroptosis](https://bliptext.com/articles/pyroptosis) of abortively infected T cells, [apoptosis](https://bliptext.com/articles/apoptosis) of uninfected bystander cells, direct viral killing of infected cells, and killing of infected CD4⁺ T cells by [CD8⁺ cytotoxic lymphocytes](https://bliptext.com/articles/cd8-cytotoxic-lymphocyte) that recognize infected cells.\nWhen CD4⁺ T cell numbers decline below a critical level, [cell-mediated immunity](https://bliptext.com/articles/cell-mediated-immunity) is lost, and the body becomes progressively more susceptible to opportunistic infections, leading to the development of AIDS.\n\n# Virology\n\n## Classification\nHIV is a member of the [genus](https://bliptext.com/articles/genus) [Lentivirus](https://bliptext.com/articles/lentivirus), part of the family [Retroviridae](https://bliptext.com/articles/retroviridae).\nLentiviruses have many [morphologies](https://bliptext.com/articles/morphology-biology) and [biological](https://bliptext.com/articles/biology) properties in common.\nMany species are infected by lentiviruses, which are characteristically responsible for long-duration illnesses with a long [incubation period](https://bliptext.com/articles/incubation-period).\nLentiviruses are transmitted as [single-stranded](https://bliptext.com/articles/single-stranded), positive-[sense](https://bliptext.com/articles/sense-molecular-biology), [enveloped](https://bliptext.com/articles/viral-envelope) [RNA viruses](https://bliptext.com/articles/rna-virus).\nUpon entry into the target cell, the viral [RNA](https://bliptext.com/articles/rna) [genome](https://bliptext.com/articles/genome) is converted (reverse transcribed) into double-stranded [DNA](https://bliptext.com/articles/dna) by a virally encoded enzyme, [reverse transcriptase](https://bliptext.com/articles/reverse-transcriptase), that is transported along with the viral [genome](https://bliptext.com/articles/genome) in the virus particle.\nThe resulting viral DNA is then imported into the [cell nucleus](https://bliptext.com/articles/cell-nucleus) and integrated into the cellular DNA by a virally encoded enzyme, [integrase](https://bliptext.com/articles/integrase), and host [co-factors](https://bliptext.com/articles/cofactor-biochemistry).\nOnce integrated, the virus may become [latent](https://bliptext.com/articles/virus-latency), allowing the virus and its host cell to avoid detection by the immune system, for an indeterminate amount of time.\nThe virus can remain dormant in the human body for up to ten years after primary infection; during this period the virus does not cause symptoms.\nAlternatively, the integrated viral DNA may be [transcribed](https://bliptext.com/articles/transcription-genetics), producing new RNA genomes and viral proteins, using host cell resources, that are packaged and released from the cell as new virus particles that will begin the replication cycle anew.\nTwo types of HIV have been characterized: HIV-1 and HIV-2.\nHIV-1 is the virus that was initially discovered and termed both lymphadenopathy associated virus (LAV) and human T-lymphotropic virus 3 (HTLV-III).\nHIV-1 is more [virulent](https://bliptext.com/articles/virulence) and more [infective](https://bliptext.com/articles/infectivity) than HIV-2, and is the cause of the majority of HIV infections globally.\nThe lower infectivity of HIV-2, compared to HIV-1, implies that fewer of those exposed to HIV-2 will be infected per exposure.\nDue to its relatively poor capacity for transmission, HIV-2 is largely confined to [West Africa](https://bliptext.com/articles/west-africa).\n\n## Structure and genome\nHIV is similar in structure to other retroviruses.\nIt is roughly spherical with a diameter of about 120 [nm](https://bliptext.com/articles/nanometre), around 100,000 times smaller in volume than a [red blood cell](https://bliptext.com/articles/red-blood-cell).\nIt is composed of two copies of positive-[sense](https://bliptext.com/articles/sense-molecular-biology) [single-stranded](https://bliptext.com/articles/single-stranded) [RNA](https://bliptext.com/articles/rna) that codes for the virus' nine [genes](https://bliptext.com/articles/gene) enclosed by a conical [capsid](https://bliptext.com/articles/capsid) composed of 2,000 copies of the viral protein [p24](https://bliptext.com/articles/p24-capsid-protein).\nThe single-stranded RNA is tightly bound to nucleocapsid proteins, p7, and enzymes needed for the development of the virion such as [reverse transcriptase](https://bliptext.com/articles/reverse-transcriptase), [proteases](https://bliptext.com/articles/protease), [ribonuclease](https://bliptext.com/articles/ribonuclease) and [integrase](https://bliptext.com/articles/integrase).\nA matrix composed of the viral protein p17 surrounds the capsid ensuring the integrity of the virion particle.\nThis is, in turn, surrounded by the [viral envelope](https://bliptext.com/articles/viral-envelope), that is composed of the [lipid bilayer](https://bliptext.com/articles/lipid-bilayer) taken from the membrane of a human host cell when the newly formed virus particle buds from the cell.\nThe viral envelope contains proteins from the host cell and relatively few copies of the HIV envelope protein, which consists of a cap made of three molecules known as [glycoprotein (gp) 120](https://bliptext.com/articles/gp120), and a stem consisting of three [gp41](https://bliptext.com/articles/gp41) molecules that anchor the structure into the viral envelope.\nThe envelope protein, encoded by the HIV env gene, allows the virus to attach to target cells and fuse the viral envelope with the target [cell's membrane](https://bliptext.com/articles/cell-membrane) releasing the viral contents into the cell and initiating the infectious cycle.\nAs the sole viral protein on the surface of the virus, the envelope protein is a major target for [HIV vaccine](https://bliptext.com/articles/hiv-vaccine) efforts.\nOver half of the mass of the trimeric envelope spike is N-linked [glycans](https://bliptext.com/articles/glycan).\nThe density is high as the glycans shield the underlying viral protein from neutralisation by antibodies.\nThis is one of the most densely glycosylated molecules known and the density is sufficiently high to prevent the normal maturation process of glycans during biogenesis in the endoplasmic and Golgi apparatus.\nThe majority of the glycans are therefore stalled as immature 'high-mannose' glycans not normally present on human glycoproteins that are secreted or present on a cell surface.\nThe unusual processing and high density means that almost all broadly neutralising antibodies that have so far been identified (from a subset of patients that have been infected for many months to years) bind to, or are adapted to cope with, these envelope glycans.\nThe molecular structure of the viral spike has now been determined by [X-ray crystallography](https://bliptext.com/articles/x-ray-crystallography) and [cryogenic electron microscopy](https://bliptext.com/articles/cryogenic-electron-microscopy).\nThese advances in structural biology were made possible due to the development of stable [recombinant](https://bliptext.com/articles/recombinant-organism) forms of the viral spike by the introduction of an intersubunit [disulphide bond](https://bliptext.com/articles/disulphide-bond) and an [isoleucine](https://bliptext.com/articles/isoleucine) to [proline](https://bliptext.com/articles/proline) [mutation](https://bliptext.com/articles/mutation) ([radical replacement](https://bliptext.com/articles/radical-replacement) of an amino acid) in gp41.\nThe so-called SOSIP [trimers](https://bliptext.com/articles/trimer-chemistry) not only reproduce the antigenic properties of the native viral spike, but also display the same degree of immature glycans as presented on the native virus.\nRecombinant trimeric viral spikes are promising vaccine candidates as they display less non-neutralising [epitopes](https://bliptext.com/articles/epitope) than recombinant monomeric gp120, which act to suppress the immune response to target [epitopes](https://bliptext.com/articles/epitope).\nThe RNA genome consists of at least seven structural landmarks ([LTR](https://bliptext.com/articles/long-terminal-repeat), [TAR](https://bliptext.com/articles/trans-activation-response-element-tar), [RRE](https://bliptext.com/articles/hiv-rev-response-element), PE, SLIP, CRS, and INS), and nine genes (gag, pol, and env, tat, rev, nef, vif, vpr, vpu, and sometimes a tenth tev, which is a fusion of tat, env and rev), encoding 19 proteins.\nThree of these genes, gag, pol, and env, contain information needed to make the structural proteins for new virus particles.\nFor example, env codes for a protein called gp160 that is cut in two by a cellular protease to form gp120 and gp41.\nThe six remaining genes, tat, rev, nef, vif, vpr, and vpu (or vpx in the case of HIV-2), are regulatory genes for proteins that control the ability of HIV to infect cells, produce new copies of virus (replicate), or cause disease.\nThe two [tat](https://bliptext.com/articles/tat-hiv) proteins (p16 and p14) are [transcriptional transactivators](https://bliptext.com/articles/activator-genetics) for the LTR [promoter](https://bliptext.com/articles/promoter-genetics) acting by binding the TAR RNA element.\nThe TAR may also be processed into [microRNAs](https://bliptext.com/articles/microrna) that regulate the [apoptosis](https://bliptext.com/articles/apoptosis) genes [ERCC1](https://bliptext.com/articles/ercc1) and [IER3](https://bliptext.com/articles/ier3).\nThe rev protein (p19) is involved in shuttling RNAs from the nucleus and the cytoplasm by binding to the [RRE](https://bliptext.com/articles/hiv-rev-response-element) RNA element.\nThe vif protein (p23) prevents the action of [APOBEC3G](https://bliptext.com/articles/apobec3g) (a cellular protein that [deaminates](https://bliptext.com/articles/deamination) [cytidine](https://bliptext.com/articles/cytidine) to [uridine](https://bliptext.com/articles/uridine) in the single-stranded viral DNA and/or interferes with reverse transcription ).\nThe [vpr](https://bliptext.com/articles/vpr) protein (p14) arrests [cell division](https://bliptext.com/articles/cell-division) at [G2/M](https://bliptext.com/articles/g2-m-checkpoint).\nThe nef protein (p27) down-regulates [CD4](https://bliptext.com/articles/cd4) (the major viral receptor), as well as the [MHC class I](https://bliptext.com/articles/mhc-class-i) and [class II](https://bliptext.com/articles/mhc-class-ii) molecules.\nNef also interacts with [SH3 domains](https://bliptext.com/articles/sh3-domain).\nThe vpu protein (p16) influences the release of new virus particles from infected cells.\nThe ends of each strand of HIV RNA contain an RNA sequence called a [long terminal repeat](https://bliptext.com/articles/long-terminal-repeat) (LTR).\nRegions in the LTR act as switches to control production of new viruses and can be triggered by proteins from either HIV or the host cell.\nThe [Psi element](https://bliptext.com/articles/retroviral-psi-packaging-element) is involved in viral genome packaging and recognized by gag and rev proteins.\nThe SLIP element is involved in the [frameshift](https://bliptext.com/articles/translational-frameshift) in the gag-pol [reading frame](https://bliptext.com/articles/reading-frame) required to make functional pol.\n# [Diagram of the HIV virion | upload.wikimedia.org/wikipedia/commons/5/5e/HI-virion-structure///en.svg]\n# [A diagram of the HIV spike protein (green), with the fusion peptide epitope highlighted in red, and a broadly neutralizing antibody (yellow) binding to the fusion peptide | upload.wikimedia.org/wikipedia/commons/8/88/Protein///Structure///Diagram///of///Fusion///Peptide///Epitope///on///HIV///Spike///%2841863579304%29.jpg]\n# [Structure of the RNA genome of HIV-1 | upload.wikimedia.org/wikipedia/commons/c/c6/HIV-genome.png]\n\n## Tropism\nThe term [viral tropism](https://bliptext.com/articles/viral-tropism) refers to the cell types a virus infects.\nHIV can infect a variety of immune cells such as [CD4⁺ T cells](https://bliptext.com/articles/helper-t-cell), [macrophages](https://bliptext.com/articles/macrophage), and [microglial cells](https://bliptext.com/articles/microglial-cell).\nHIV-1 entry to macrophages and CD4⁺ T cells is mediated through interaction of the virion envelope glycoproteins (gp120) with the CD4 molecule on the target cells' membrane and also with [chemokine](https://bliptext.com/articles/chemokine) [co-receptors](https://bliptext.com/articles/co-receptor).\nMacrophage-tropic (M-tropic) strains of HIV-1, or non-[syncytia](https://bliptext.com/articles/syncytia)-inducing strains (NSI; now called R5 viruses ) use the β-chemokine receptor, [CCR5](https://bliptext.com/articles/ccr5), for entry and are thus able to replicate in both macrophages and CD4⁺ T cells.\nThis CCR5 co-receptor is used by almost all primary HIV-1 isolates regardless of viral genetic subtype.\nIndeed, macrophages play a key role in several critical aspects of HIV infection.\nThey appear to be the first cells infected by HIV and perhaps the source of HIV production when CD4⁺ cells become depleted in the patient.\nMacrophages and microglial cells are the cells infected by HIV in the [central nervous system](https://bliptext.com/articles/central-nervous-system).\nIn the [tonsils](https://bliptext.com/articles/tonsil) and [adenoids](https://bliptext.com/articles/adenoids) of HIV-infected patients, macrophages fuse into multinucleated [giant cells](https://bliptext.com/articles/giant-cell) that produce huge amounts of virus.\nT-tropic strains of HIV-1, or [syncytia](https://bliptext.com/articles/syncytia)-inducing strains (SI; now called X4 viruses ) replicate in primary CD4⁺ T cells as well as in macrophages and use the α-chemokine receptor, [CXCR4](https://bliptext.com/articles/cxcr4), for entry.\nDual-tropic HIV-1 strains are thought to be transitional strains of HIV-1 and thus are able to use both CCR5 and CXCR4 as co-receptors for viral entry.\nThe α-chemokine [SDF-1](https://bliptext.com/articles/sdf-1-biology), a [ligand](https://bliptext.com/articles/ligand-biochemistry) for CXCR4, suppresses replication of T-tropic HIV-1 isolates.\nIt does this by [down-regulating](https://bliptext.com/articles/downregulation-and-upregulation) the expression of CXCR4 on the surface of HIV target cells.\nM-tropic HIV-1 isolates that use only the CCR5 receptor are termed R5; those that use only CXCR4 are termed X4, and those that use both, X4R5.\nHowever, the use of co-receptors alone does not explain viral tropism, as not all R5 viruses are able to use CCR5 on macrophages for a productive infection and HIV can also infect a subtype of [myeloid dendritic cells](https://bliptext.com/articles/myeloid-dendritic-cells), which probably constitute a [reservoir](https://bliptext.com/articles/natural-reservoir) that maintains infection when CD4⁺ T cell numbers have declined to extremely low levels.\nSome people are resistant to certain strains of HIV.\nFor example, people with the [CCR5-Δ32](https://bliptext.com/articles/ccr5-32) mutation are resistant to infection by the R5 virus, as the mutation leaves HIV unable to bind to this co-receptor, reducing its ability to infect target cells.\n[Sexual intercourse](https://bliptext.com/articles/sexual-intercourse) is the major mode of HIV transmission.\nBoth X4 and R5 HIV are present in the [seminal fluid](https://bliptext.com/articles/seminal-fluid), which enables the virus to be transmitted from a male to his [sexual partner](https://bliptext.com/articles/sexual-partner).\nThe virions can then infect numerous cellular targets and disseminate into the whole organism.\nHowever, a selection process leads to a predominant transmission of the R5 virus through this pathway.\nIn patients infected with subtype B HIV-1, there is often a co-receptor switch in late-stage disease and T-tropic variants that can infect a variety of T cells through CXCR4.\nThese variants then replicate more aggressively with heightened virulence that causes rapid T cell depletion, immune system collapse, and opportunistic infections that mark the advent of AIDS.\nHIV-positive patients acquire an enormously broad spectrum of opportunistic infections, which was particularly problematic prior to the onset of [HAART](https://bliptext.com/articles/management-of-hiv-aids) therapies; however, the same infections are reported among HIV-infected patients examined post-mortem following the onset of antiretroviral therapies.\nThus, during the course of infection, viral adaptation to the use of CXCR4 instead of CCR5 may be a key step in the progression to AIDS.\nA number of studies with subtype B-infected individuals have determined that between 40 and 50 percent of AIDS patients can harbour viruses of the SI and, it is presumed, the X4 phenotypes.\nHIV-2 is much less pathogenic than HIV-1 and is restricted in its worldwide distribution to [West Africa](https://bliptext.com/articles/west-africa).\nThe adoption of \"accessory genes\" by HIV-2 and its more [promiscuous](https://bliptext.com/articles/enzyme-promiscuity) pattern of co-receptor usage (including CD4-independence) may assist the virus in its adaptation to avoid innate restriction factors present in host cells.\nAdaptation to use normal cellular machinery to enable transmission and productive infection has also aided the establishment of HIV-2 replication in humans.\nA survival strategy for any infectious agent is not to kill its host, but ultimately become a [commensal](https://bliptext.com/articles/commensal) organism.\nHaving achieved a low pathogenicity, over time, variants that are more successful at transmission will be selected.\n# [Diagram of the immature and mature forms of HIV | upload.wikimedia.org/wikipedia/commons/0/00/HIV///Mature///and///Immature.PNG]\n\n## Replication cycle\n# [The HIV replication cycle | upload.wikimedia.org/wikipedia/commons/5/57/HIV-replication-cycle-en.svg]\n\n### Entry to the cell\nThe HIV virion enters [macrophages](https://bliptext.com/articles/macrophage) and CD4⁺ [T cells](https://bliptext.com/articles/t-cells) by the [adsorption](https://bliptext.com/articles/adsorption) of [glycoproteins](https://bliptext.com/articles/glycoprotein) on its surface to receptors on the target cell followed by fusion of the [viral envelope](https://bliptext.com/articles/viral-envelope) with the target cell membrane and the release of the HIV capsid into the cell.\nEntry to the cell begins through interaction of the trimeric envelope complex ([gp160](https://bliptext.com/articles/gp160) spike) on the HIV viral envelope and both [CD4](https://bliptext.com/articles/cd4) and a chemokine co-receptor (generally either [CCR5](https://bliptext.com/articles/ccr5) or [CXCR4](https://bliptext.com/articles/cxcr4), but others are known to interact) on the target cell surface.\nGp120 binds to [integrin](https://bliptext.com/articles/integrin) α4β7 activating [LFA-1](https://bliptext.com/articles/lfa-1), the central [integrin](https://bliptext.com/articles/integrin) involved in the establishment of [virological synapses](https://bliptext.com/articles/virological-synapse), which facilitate efficient cell-to-cell spreading of HIV-1.\nThe gp160 spike contains binding domains for both CD4 and chemokine receptors.\nThe first step in fusion involves the high-affinity attachment of the CD4 binding domains of [gp120](https://bliptext.com/articles/gp120) to CD4.\nOnce gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine receptor binding domains of gp120 and allowing them to interact with the target chemokine receptor.\nThis allows for a more stable two-pronged attachment, which allows the [N-terminal](https://bliptext.com/articles/n-terminus) fusion peptide gp41 to penetrate the cell membrane.\n[Repeat sequences](https://bliptext.com/articles/repeated-sequence-dna) in gp41, HR1, and HR2 then interact, causing the collapse of the extracellular portion of gp41 into a hairpin shape.\nThis loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.\nAfter HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase, ribonuclease, and protease, are injected into the cell.\nDuring the [microtubule](https://bliptext.com/articles/microtubule)-based transport to the nucleus, the viral single-strand RNA genome is transcribed into double-strand DNA, which is then integrated into a host chromosome.\nHIV can infect [dendritic cells](https://bliptext.com/articles/dendritic-cell) (DCs) by this CD4-CCR5 route, but another route using [mannose-specific C-type lectin receptors](https://bliptext.com/articles/mannose-receptor) such as [DC-SIGN](https://bliptext.com/articles/dc-sign) can also be used.\nDCs are one of the first cells encountered by the virus during sexual transmission.\nThey are currently thought to play an important role by transmitting HIV to T cells when the virus is captured in the [mucosa](https://bliptext.com/articles/mucosa) by DCs.\nThe presence of [FEZ-1](https://bliptext.com/articles/fez-1), which occurs naturally in [neurons](https://bliptext.com/articles/neuron), is believed to prevent the infection of cells by HIV.\nHIV-1 entry, as well as entry of many other retroviruses, has long been believed to occur exclusively at the plasma membrane.\nMore recently, however, productive infection by [pH](https://bliptext.com/articles/ph)-independent, [clathrin-mediated endocytosis](https://bliptext.com/articles/clathrin-mediated-endocytosis) of HIV-1 has also been reported and was recently suggested to constitute the only route of productive entry.\n# [Mechanism of viral entry: 1. Initial interaction between gp120 and CD4. 2. Conformational change in gp120 allows for secondary interaction with CXCR4. 3. The distal tips of gp41 are inserted into the cellular membrane. 4. gp41 undergoes significant conformational change; folding in half and forming coiled-coils. This process pulls the viral and cellular membranes together, fusing them. | upload.wikimedia.org/wikipedia/commons/6/61/HIV///Membrane///fusion///panel.svg]\n# [Clathrin-mediated endocytosis | upload.wikimedia.org/wikipedia/commons/4/47/Itrafig2.jpg]\n\n### Replication and transcription\nShortly after the viral capsid enters the cell, an [enzyme](https://bliptext.com/articles/enzyme) called [reverse transcriptase](https://bliptext.com/articles/reverse-transcriptase) liberates the positive-sense single-stranded [RNA](https://bliptext.com/articles/rna) genome from the attached viral proteins and copies it into a [complementary DNA](https://bliptext.com/articles/cdna) (cDNA) molecule.\nThe process of reverse transcription is extremely error-prone, and the resulting mutations may cause [drug resistance](https://bliptext.com/articles/resistance-to-antiviral-drugs) or allow the virus to evade the body's immune system.\nThe reverse transcriptase also has ribonuclease activity that degrades the viral RNA during the synthesis of cDNA, as well as DNA-dependent DNA polymerase activity that creates a [sense](https://bliptext.com/articles/sense-molecular-biology) DNA from the anti[sense](https://bliptext.com/articles/sense-molecular-biology) cDNA.\nTogether, the cDNA and its complement form a double-stranded viral DNA that is then transported into the [cell nucleus](https://bliptext.com/articles/cell-nucleus).\nThe integration of the viral DNA into the host cell's [genome](https://bliptext.com/articles/genome) is carried out by another viral enzyme called [integrase](https://bliptext.com/articles/integrase).\nThe integrated viral DNA may then lie dormant, in the latent stage of HIV infection.\nTo actively produce the virus, certain cellular [transcription factors](https://bliptext.com/articles/transcription-factor) need to be present, the most important of which is NF-κB (nuclear factor kappa B), which is upregulated when T cells become activated.\nThis means that those cells most likely to be targeted, entered and subsequently killed by HIV are those actively fighting infection.\nDuring viral replication, the integrated DNA [provirus](https://bliptext.com/articles/provirus) is [transcribed](https://bliptext.com/articles/transcription-genetics) into RNA.\nThe full-length genomic RNAs (gRNA) can be packaged into new viral particles in a [pseudodiploid](https://bliptext.com/articles/pseudodiploid) form.\nThe selectivity in the packaging is explained by the structural properties of the dimeric conformer of the gRNA.\nThe gRNA dimer is characterized by a tandem three-way junction within the gRNA monomer, in which the SD and AUG [hairpins](https://bliptext.com/articles/stem-loop), responsible for splicing and translation respectively, are sequestered and the DIS (dimerization initiation signal) hairpin is exposed.\nThe formation of the gRNA dimer is mediated by a 'kissing' interaction between the DIS hairpin loops of the gRNA monomers.\nAt the same time, certain guanosine residues in the gRNA are made available for binding of the nucleocapsid (NC) protein leading to the subsequent virion assembly.\nThe labile gRNA dimer has been also reported to achieve a more stable conformation following the NC binding, in which both the DIS and the U5:AUG regions of the gRNA participate in extensive base pairing.\nRNA can also be [processed](https://bliptext.com/articles/post-transcriptional-modification) to produce mature [messenger RNAs](https://bliptext.com/articles/messenger-rna) (mRNAs).\nIn most cases, this processing involves [RNA splicing](https://bliptext.com/articles/rna-splicing) to produce mRNAs that are shorter than the full-length genome.\nWhich part of the RNA is removed during RNA splicing determines which of the HIV protein-coding sequences is translated.\nMature HIV mRNAs are exported from the nucleus into the [cytoplasm](https://bliptext.com/articles/cytoplasm), where they are [translated](https://bliptext.com/articles/translation-genetics) to produce HIV proteins, including [Rev](https://bliptext.com/articles/rev-hiv).\nAs the newly produced Rev protein is produced it moves to the nucleus, where it binds to full-length, unspliced copies of virus RNAs and allows them to leave the nucleus.\nSome of these full-length RNAs function as mRNAs that are translated to produce the structural proteins Gag and Env.\nGag proteins bind to copies of the virus RNA genome to package them into new virus particles.\nHIV-1 and HIV-2 appear to package their RNA differently.\nHIV-1 will bind to any appropriate RNA.\nHIV-2 will preferentially bind to the mRNA that was used to create the Gag protein itself.\n# [Reverse transcription of the HIV genome into double-stranded DNA | upload.wikimedia.org/wikipedia/commons/a/aa/Reverse///Transcription.png]\n\n### Recombination\nTwo RNA genomes are encapsidated in each HIV-1 particle (see [Structure and genome of HIV](https://bliptext.com/articles/structure-and-genome-of-hiv)).\nUpon infection and replication catalyzed by reverse transcriptase, recombination between the two genomes can occur.\nRecombination occurs as the single-strand, positive-sense RNA genomes are reverse transcribed to form DNA.\nDuring reverse transcription, the nascent DNA can switch multiple times between the two copies of the viral RNA.\nThis form of recombination is known as copy-choice.\nRecombination events may occur throughout the genome.\nAnywhere from two to 20 recombination events per genome may occur at each replication cycle, and these events can rapidly shuffle the genetic information that is transmitted from parental to progeny genomes.\nViral recombination produces genetic variation that likely contributes to the [evolution](https://bliptext.com/articles/evolution) of resistance to [anti-retroviral therapy](https://bliptext.com/articles/management-of-hiv-aids).\nRecombination may also contribute, in principle, to overcoming the immune defenses of the host.\nYet, for the adaptive advantages of genetic variation to be realized, the two viral genomes packaged in individual infecting virus particles need to have arisen from separate progenitor parental viruses of differing genetic constitution.\nIt is unknown how often such mixed packaging occurs under natural conditions.\nBonhoeffer et al. suggested that template switching by reverse transcriptase acts as a repair process to deal with breaks in the single-stranded RNA genome.\nIn addition, Hu and Temin suggested that recombination is an adaptation for repair of damage in the RNA genomes.\nStrand switching (copy-choice recombination) by reverse transcriptase could generate an undamaged copy of genomic DNA from two damaged single-stranded RNA genome copies.\nThis view of the adaptive benefit of recombination in HIV could explain why each HIV particle contains two complete genomes, rather than one.\nFurthermore, the view that recombination is a repair process implies that the benefit of repair can occur at each replication cycle, and that this benefit can be realized whether or not the two genomes differ genetically.\nOn the view that recombination in HIV is a repair process, the generation of recombinational variation would be a consequence, but not the cause of, the evolution of template switching.\nHIV-1 infection causes [chronic inflammation](https://bliptext.com/articles/chronic-inflammation) and production of [reactive oxygen species](https://bliptext.com/articles/reactive-oxygen-species).\nThus, the HIV genome may be vulnerable to [oxidative damage](https://bliptext.com/articles/oxidative-damage), including breaks in the single-stranded RNA.\nFor HIV, as well as for viruses in general, successful infection depends on overcoming host defense strategies that often include production of genome-damaging reactive oxygen species.\nThus, Michod et al. suggested that recombination by viruses is an adaptation for repair of genome damage, and that recombinational variation is a byproduct that may provide a separate benefit.\n\n### Assembly and release\nThe final step of the viral cycle, assembly of new HIV-1 virions, begins at the [plasma membrane](https://bliptext.com/articles/plasma-membrane) of the host cell.\nThe Env polyprotein (gp160) goes through the [endoplasmic reticulum](https://bliptext.com/articles/endoplasmic-reticulum) and is transported to the [Golgi apparatus](https://bliptext.com/articles/golgi-apparatus) where it is [cleaved](https://bliptext.com/articles/bond-cleavage) by [furin](https://bliptext.com/articles/furin) resulting in the two HIV envelope glycoproteins, [gp41](https://bliptext.com/articles/gp41) and [gp120](https://bliptext.com/articles/gp120).\nThese are transported to the plasma membrane of the host cell where gp41 anchors gp120 to the membrane of the infected cell.\nThe Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the HIV genomic RNA as the forming virion begins to bud from the host cell.\nThe budded virion is still immature as the [gag](https://bliptext.com/articles/group-specific-antigen) polyproteins still need to be cleaved into the actual matrix, capsid and nucleocapsid proteins.\nThis cleavage is mediated by the packaged viral protease and can be inhibited by antiretroviral drugs of the [protease inhibitor](https://bliptext.com/articles/protease-inhibitor-pharmacology) class.\nThe various structural components then assemble to produce a mature HIV virion.\nOnly mature virions are then able to infect another cell.\n# [HIV assembling on the surface of an infected macrophage. The HIV virions have been marked with a green fluorescent tag and then viewed under a fluorescent microscope. | upload.wikimedia.org/wikipedia/commons/a/a7/HIV///on///macrophage.png]\n\n## Spread within the body\nThe classical process of infection of a cell by a virion can be called \"cell-free spread\" to distinguish it from a more recently recognized process called \"cell-to-cell spread\".\nIn cell-free spread (see figure), virus particles bud from an infected T cell, enter the blood or [extracellular fluid](https://bliptext.com/articles/extracellular-fluid) and then infect another T cell following a chance encounter.\nHIV can also disseminate by direct transmission from one cell to another by a process of cell-to-cell spread, for which two pathways have been described.\nFirstly, an infected T cell can transmit virus directly to a target T cell via a [virological synapse](https://bliptext.com/articles/viral-synapse).\nSecondly, an [antigen-presenting cell](https://bliptext.com/articles/antigen-presenting-cell) (APC), such as a macrophage or dendritic cell, can transmit HIV to T cells by a process that either involves productive infection (in the case of macrophages) or capture and transfer of virions in trans (in the case of dendritic cells).\nWhichever pathway is used, infection by cell-to-cell transfer is reported to be much more efficient than cell-free virus spread.\nA number of factors contribute to this increased efficiency, including polarised virus budding towards the site of cell-to-cell contact, close apposition of cells, which minimizes fluid-phase [diffusion](https://bliptext.com/articles/diffusion) of virions, and clustering of HIV entry receptors on the target cell towards the contact zone.\nCell-to-cell spread is thought to be particularly important in [lymphoid tissues](https://bliptext.com/articles/lymphoid-tissue), where CD4+ T cells are densely packed and likely to interact frequently.\n[Intravital imaging](https://bliptext.com/articles/intravital-microscopy) studies have supported the concept of the HIV virological synapse in vivo.\nThe many dissemination mechanisms available to HIV contribute to the virus' ongoing replication in spite of anti-retroviral therapies.\n\n## Genetic variability\nHIV differs from many viruses in that it has very high [genetic variability](https://bliptext.com/articles/genetic-variability).\nThis diversity is a result of its fast [replication cycle](https://bliptext.com/articles/), with the generation of about 1010 virions every day, coupled with a high [mutation rate](https://bliptext.com/articles/mutation-rate) of approximately 3 x 10−5 per [nucleotide base](https://bliptext.com/articles/nucleobase) per cycle of replication and [recombinogenic](https://bliptext.com/articles/genetic-recombination) properties of reverse transcriptase.\nThis complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day.\nThis variability is compounded when a single cell is simultaneously infected by two or more different strains of HIV.\nWhen [simultaneous infection](https://bliptext.com/articles/coinfection) occurs, the genome of progeny virions may be composed of RNA strands from two different strains.\nThis hybrid virion then infects a new cell where it undergoes replication.\nAs this happens, the reverse transcriptase, by jumping back and forth between the two different RNA templates, will generate a newly synthesized retroviral [DNA sequence](https://bliptext.com/articles/dna-sequence) that is a recombinant between the two parental genomes.\nThis recombination is most obvious when it occurs between subtypes.\nThe closely related [simian immunodeficiency virus](https://bliptext.com/articles/simian-immunodeficiency-virus) (SIV) has evolved into many strains, classified by the natural host species.\nSIV strains of the [African green monkey](https://bliptext.com/articles/chlorocebus) (SIVagm) and [sooty mangabey](https://bliptext.com/articles/sooty-mangabey) (SIVsmm) are thought to have a long evolutionary history with their hosts.\nThese hosts have adapted to the presence of the virus, which is present at high levels in the host's blood, but evokes only a mild immune response, does not cause the development of simian AIDS, and does not undergo the extensive mutation and recombination typical of HIV infection in humans.\nIn contrast, when these strains infect species that have not adapted to SIV (\"heterologous\" or similar hosts such as [rhesus](https://bliptext.com/articles/rhesus-macaque) or [cynomologus macaques](https://bliptext.com/articles/crab-eating-macaque)), the animals develop AIDS and the virus generates [genetic diversity](https://bliptext.com/articles/genetic-diversity) similar to what is seen in human HIV infection.\n[Chimpanzee](https://bliptext.com/articles/common-chimpanzee) SIV (SIVcpz), the closest genetic relative of HIV-1, is associated with increased mortality and AIDS-like symptoms in its natural host.\nSIVcpz appears to have been transmitted relatively recently to chimpanzee and human populations, so their hosts have not yet adapted to the virus.\nThis virus has also lost a function of the [nef](https://bliptext.com/articles/nef-protein) gene that is present in most SIVs.\nFor non-pathogenic SIV variants, nef suppresses T cell activation through the [CD3](https://bliptext.com/articles/cd3-immunology) marker.\nNef function in non-pathogenic forms of SIV is to [downregulate](https://bliptext.com/articles/downregulation-and-upregulation) expression of [inflammatory cytokines](https://bliptext.com/articles/proinflammatory-cytokine), [MHC-1](https://bliptext.com/articles/mhc-class-i), and signals that affect T cell trafficking.\nIn HIV-1 and SIVcpz, nef does not inhibit T-cell activation and it has lost this function.\nWithout this function, T cell depletion is more likely, leading to immunodeficiency.\nThree groups of HIV-1 have been identified on the basis of differences in the envelope (env) region: M, N, and O. Group M is the most prevalent and is subdivided into eight subtypes (or [clades](https://bliptext.com/articles/clade)), based on the whole genome, which are geographically distinct.\nThe most prevalent are subtypes B (found mainly in North America and Europe), A and D (found mainly in Africa), and C (found mainly in Africa and Asia); these subtypes form branches in the [phylogenetic tree](https://bliptext.com/articles/phylogenetic-tree) representing the lineage of the M group of HIV-1.\n[Co-infection](https://bliptext.com/articles/coinfection) with distinct subtypes gives rise to circulating recombinant forms (CRFs).\nIn 2000, the last year in which an analysis of global subtype prevalence was made, 47.2% of infections worldwide were of subtype C, 26.7% were of subtype A/CRF02_AG, 12.3% were of subtype B, 5.3% were of subtype D, 3.2% were of CRF_AE, and the remaining 5.3% were composed of other subtypes and CRFs.\nMost HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes.\nThe existence of a fourth group, \"P\", has been hypothesised based on a virus isolated in 2009.\nThe strain is apparently derived from [gorilla](https://bliptext.com/articles/gorilla-gorilla) SIV (SIVgor), first isolated from western lowland [gorilla](https://bliptext.com/articles/gorilla-gorilla)s in 2006.\nHIV-2's closest relative is SIVsm, a strain of SIV found in sooty mangabees.\nSince HIV-1 is derived from SIVcpz, and HIV-2 from SIVsm, the genetic sequence of HIV-2 is only partially homologous to HIV-1 and more closely resembles that of SIVsm.\n# [The phylogenetic tree of the SIV and HIV | upload.wikimedia.org/wikipedia/commons/f/fb/HIV-SIV-phylogenetic-tree///straight.svg]\n\n# Diagnosis\nMany HIV-positive people are unaware that they are infected with the virus.\nFor example, in 2001 less than 1% of the sexually active urban population in Africa had been tested, and this proportion is even lower in rural populations.\nFurthermore, in 2001 only 0.5% of [pregnant women](https://bliptext.com/articles/pregnancy) attending urban health facilities were counselled, tested or received their test results.\nAgain, this proportion is even lower in rural health facilities.\nSince donors may therefore be unaware of their infection, [donor blood](https://bliptext.com/articles/blood-donation) and blood products used in medicine and [medical research](https://bliptext.com/articles/medical-research) are routinely screened for HIV.\nHIV-1 testing is initially done using an [enzyme-linked immunosorbent assay](https://bliptext.com/articles/enzyme-linked-immunosorbent-assay) (ELISA) to detect antibodies to HIV-1.\nSpecimens with a non-reactive result from the initial ELISA are considered HIV-negative, unless new exposure to an infected partner or partner of unknown HIV status has occurred.\nSpecimens with a reactive ELISA result are retested in duplicate.\nIf the result of either duplicate test is reactive, the specimen is reported as repeatedly reactive and undergoes confirmatory testing with a more specific supplemental test (e.g., a [polymerase chain reaction](https://bliptext.com/articles/polymerase-chain-reaction) (PCR), [western blot](https://bliptext.com/articles/western-blot) or, less commonly, an [immunofluorescence assay](https://bliptext.com/articles/immunofluorescence-assay) (IFA)).\nOnly specimens that are repeatedly reactive by ELISA and positive by IFA or PCR or reactive by western blot are considered HIV-positive and indicative of HIV infection.\nSpecimens that are repeatedly ELISA-reactive occasionally provide an indeterminate western blot result, which may be either an incomplete antibody response to HIV in an infected person or nonspecific reactions in an uninfected person.\nAlthough IFA can be used to confirm infection in these ambiguous cases, this assay is not widely used.\nIn general, a second specimen should be collected more than a month later and retested for persons with indeterminate western blot results.\nAlthough much less commonly available, [nucleic acid testing](https://bliptext.com/articles/nucleic-acid-test) (e.g., viral RNA or proviral DNA amplification method) can also help diagnosis in certain situations.\nIn addition, a few tested specimens might provide inconclusive results because of a low quantity specimen.\nIn these situations, a second specimen is collected and tested for HIV infection.\nModern HIV testing is extremely accurate, when the [window period](https://bliptext.com/articles/window-period) is taken into consideration.\nA single screening test is correct more than 99% of the time.\nThe chance of a false-positive result in a standard two-step testing protocol is estimated to be about 1 in 250,000 in a low risk population.\nTesting post-exposure is recommended immediately and then at six weeks, three months, and six months.\nThe latest recommendations of the US [Centers for Disease Control and Prevention](https://bliptext.com/articles/centers-for-disease-control-and-prevention-cdc) (CDC) show that HIV testing must start with an [immunoassay](https://bliptext.com/articles/immunoassay) combination test for HIV-1 and HIV-2 [antibodies](https://bliptext.com/articles/antibody) and p24 [antigen](https://bliptext.com/articles/antigen).\nA negative result rules out HIV exposure, while a positive one must be followed by an HIV-1/2 antibody differentiation immunoassay to detect which antibodies are present.\nThis gives rise to four possible scenarios:\n# [A generalized graph of the relationship between HIV copies (viral load) and CD4 counts over the average course of untreated HIV infection; any particular individual's disease course may vary considerably. | upload.wikimedia.org/wikipedia/commons/0/0e/Hiv-timecourse///copy.svg]\n\n# Research\n[HIV/AIDS](https://bliptext.com/articles/hiv-aids) research includes all [medical research](https://bliptext.com/articles/medical-research) that attempts to prevent, treat, or cure [HIV/AIDS](https://bliptext.com/articles/hiv-aids), as well as fundamental research about the nature of HIV as an infectious agent and AIDS as the disease caused by HIV.\nMany governments and research institutions participate in HIV/AIDS research.\nThis research includes behavioral [health interventions](https://bliptext.com/articles/health-interventions), such as research into [sex education](https://bliptext.com/articles/sex-education), and [drug development](https://bliptext.com/articles/drug-development), such as research into [microbicides for sexually transmitted diseases](https://bliptext.com/articles/microbicides-for-sexually-transmitted-diseases), [HIV vaccines](https://bliptext.com/articles/hiv-vaccine), and [anti-retroviral drugs](https://bliptext.com/articles/antiretroviral-drug).\nOther medical research areas include the topics of [pre-exposure prophylaxis](https://bliptext.com/articles/pre-exposure-prophylaxis), [post-exposure prophylaxis](https://bliptext.com/articles/post-exposure-prophylaxis), [circumcision](https://bliptext.com/articles/circumcision-and-hiv), and [accelerated aging effects](https://bliptext.com/articles/biological-clock-aging).\n\n# Treatment and transmission\nThe management of HIV/AIDS typically involves the use of multiple [antiretroviral drugs](https://bliptext.com/articles/antiretroviral-drugs).\nIn many parts of the world, HIV has become a chronic condition, with progression to [AIDS](https://bliptext.com/articles/aids) increasingly rare.\n[HIV latency](https://bliptext.com/articles/hiv-latency) and the resulting [viral reservoir](https://bliptext.com/articles/viral-reservoir) in CD4+ T cells, dendritic cells, and macrophages is the main barrier to eradication of the virus.\nWhile HIV is highly virulent, transmission through sexual contact does not occur when an HIV-positive individual maintains a consistently undetectable [viral load](https://bliptext.com/articles/viral-load) (<50 copies/ml) due to antiretroviral treatment.\nThis concept was first proposed by the Swiss Federal Commission for AIDS/HIV in 2008 in what is known as the [Swiss Statement](https://bliptext.com/articles/swiss-statement).\nAlthough initially controversial, subsequent studies have confirmed that the risk of transmitting HIV through sex is effectively zero when the HIV-positive person has a consistently undetectable viral load, a concept now widely known as U=U, or \"Undetectable = Untransmittable.\"\nStudies that established the U=U principle include Opposites Attract, PARTNER 1, PARTNER 2 (which focused on male-male couples), and [HPTN052](https://bliptext.com/articles/hptn-052) (which focused on heterosexual couples).\nThese studies involved couples where one partner was HIV-positive and one was HIV-negative, and included regular HIV testing.\nAcross these four studies, a total of 4,097 couples participated from four continents, reporting 151,880 acts of condomless sex with zero phylogenetically-linked HIV transmissions when the positive partner had an undetectable viral load.\nFollowing these findings, the U=U consensus statement advocating the use of the term 'zero risk' was endorsed by numerous individuals and organizations, including the [CDC](https://bliptext.com/articles/cdc), the [British HIV Association](https://bliptext.com/articles/british-hiv-association), and [The Lancet](https://bliptext.com/articles/the-lancet) medical journal.\nAdditionally, reactivation of [herpes simplex virus-2](https://bliptext.com/articles/herpes-simplex-virus-2) (HSV-2) in individuals with [genital herpes](https://bliptext.com/articles/genital-herpes) is associated with an increase in [CCR-5](https://bliptext.com/articles/ccr5) enriched CD4+ T cells and inflammatory dendritic cells in the dermis of ulcerated genital skin, persisting even after ulcer healing.\nHIV's tropism for CCR-5 positive cells contributes to the two- to threefold increased risk of HIV acquisition in persons with genital herpes.\nNotably, daily antiviral medication, such as [acyclovir](https://bliptext.com/articles/acyclovir), does not reduce the subclinical post-reactivation inflammation and therefore does not decrease the risk of HIV acquisition.\n\n# History\n\n## Discovery\nThe first news story on \"an exotic new disease\" appeared May 18, 1981, in the gay newspaper [New York Native](https://bliptext.com/articles/new-york-native).\nAIDS was first clinically observed in 1981 in the United States.\nThe initial cases were a cluster of injection drug users and gay men with no known cause of impaired immunity who showed symptoms of [Pneumocystis](https://bliptext.com/articles/pneumocystis-jirovecii) pneumonia (PCP or PJP, the latter term recognizing that the causative agent is now called [Pneumocystis](https://bliptext.com/articles/pneumocystis-jirovecii) jirovecii), a rare opportunistic infection that was known to occur in people with very compromised immune systems.\nSoon thereafter, researchers at the [NYU School of Medicine](https://bliptext.com/articles/nyu-school-of-medicine) studied gay men developing a previously rare skin cancer called [Kaposi's sarcoma](https://bliptext.com/articles/kaposi-s-sarcoma) (KS).\nMany more cases of PJP and KS emerged, alerting U.S. [Centers for Disease Control and Prevention](https://bliptext.com/articles/centers-for-disease-control-and-prevention) (CDC) and a CDC task force was formed to monitor the outbreak.\nThe earliest retrospectively described case of AIDS is believed to have been in Norway beginning in 1966.\nIn the beginning, the CDC did not have an official name for the disease, often referring to it by way of the diseases that were associated with it, for example, [lymphadenopathy](https://bliptext.com/articles/lymphadenopathy), the disease after which the discoverers of HIV originally named the virus.\nThey also used Kaposi's Sarcoma and Opportunistic Infections, the name by which a task force had been set up in 1981.\nIn the general press, the term GRID, which stood for [gay-related immune deficiency](https://bliptext.com/articles/gay-related-immune-deficiency), had been coined.\nThe CDC, in search of a name and looking at the infected communities, coined \"the 4H disease\", as it seemed to single out homosexuals, heroin users, [hemophiliacs](https://bliptext.com/articles/haemophilia), and [Haitians](https://bliptext.com/articles/haiti).\nHowever, after determining that AIDS was not isolated to the [gay community](https://bliptext.com/articles/gay-community), it was realized that the term GRID was misleading and AIDS was introduced at a meeting in July 1982.\nBy September 1982 the CDC started using the name AIDS.\nIn 1983, two separate research groups led by American [Robert Gallo](https://bliptext.com/articles/robert-gallo) and French investigators Françoise Barré-Sinoussi and [Luc Montagnier](https://bliptext.com/articles/luc-montagnier) independently declared that a novel retrovirus may have been infecting AIDS patients, and published their findings in the same issue of the journal [Science](https://bliptext.com/articles/science-journal).\nGallo claimed that a virus his group had isolated from a person with AIDS was strikingly similar in [shape](https://bliptext.com/articles/virus-structure) to other [human T-lymphotropic viruses](https://bliptext.com/articles/human-t-lymphotropic-virus) (HTLVs) his group had been the first to isolate.\nGallo admitted in 1987 that the virus he claimed to have discovered in 1984 was in reality a virus sent to him from France the year before.\nGallo's group called their newly isolated virus HTLV-III.\nMontagnier's group isolated a virus from a patient presenting with swelling of the [lymph nodes](https://bliptext.com/articles/lymph-node) of the neck and [physical weakness](https://bliptext.com/articles/asthenia), two classic symptoms of primary HIV infection.\nContradicting the report from Gallo's group, Montagnier and his colleagues showed that core proteins of this virus were immunologically different from those of HTLV-I.\nMontagnier's group named their isolated virus lymphadenopathy-associated virus (LAV).\nAs these two viruses turned out to be the same, in 1986 LAV and HTLV-III were renamed HIV.\nAnother group working contemporaneously with the Montagnier and Gallo groups was that of [Jay A. Levy](https://bliptext.com/articles/jay-a-levy) at the [University of California, San Francisco](https://bliptext.com/articles/university-of-california-san-francisco).\nHe independently discovered the AIDS virus in 1983 and named it the AIDS associated retrovirus (ARV).\nThis virus was very different from the virus reported by the Montagnier and Gallo groups.\nThe ARV strains indicated, for the first time, the heterogeneity of HIV isolates and several of these remain classic examples of the AIDS virus found in the United States.\n\n## Origins\nBoth HIV-1 and HIV-2 are believed to have originated in non-human [primates](https://bliptext.com/articles/primate) in West-central Africa, and are believed to have transferred to humans (a process known as [zoonosis](https://bliptext.com/articles/zoonosis)) in the early 20th century.\nHIV-1 appears to have originated in southern [Cameroon](https://bliptext.com/articles/cameroon) through the evolution of SIVcpz, a [simian immunodeficiency virus](https://bliptext.com/articles/simian-immunodeficiency-virus) (SIV) that infects wild [chimpanzees](https://bliptext.com/articles/common-chimpanzee) (HIV-1 descends from the SIVcpz endemic in the chimpanzee subspecies [Pan troglodytes troglodytes](https://bliptext.com/articles/central-chimpanzee)).\nThe closest relative of HIV-2 is SIVsmm, a virus of the [sooty mangabey](https://bliptext.com/articles/sooty-mangabey) (Cercocebus atys atys), an [Old World monkey](https://bliptext.com/articles/old-world-monkey) living in littoral West Africa (from southern [Senegal](https://bliptext.com/articles/senegal) to western [Côte d'Ivoire](https://bliptext.com/articles/ivory-coast)).\n[New World monkeys](https://bliptext.com/articles/new-world-monkey) such as the [owl monkey](https://bliptext.com/articles/night-monkey) are resistant to HIV-1 infection, possibly because of a [genomic fusion](https://bliptext.com/articles/fusion-gene) of two viral resistance genes.\nHIV-1 is thought to have jumped the species barrier on at least three separate occasions, giving rise to the three groups of the virus, M, N, and O.\nThere is evidence that humans who participate in [bushmeat](https://bliptext.com/articles/bushmeat) activities, either as hunters or as [bushmeat](https://bliptext.com/articles/bushmeat) vendors, commonly acquire SIV.\nHowever, SIV is a weak virus, and it is typically suppressed by the human immune system within weeks of infection.\nIt is thought that several transmissions of the virus from individual to individual in quick succession are necessary to allow it enough time to mutate into HIV.\nFurthermore, due to its relatively low person-to-person transmission rate, it can only spread throughout the population in the presence of one or more high-risk transmission channels, which are thought to have been absent in Africa prior to the 20th century.\nSpecific proposed high-risk transmission channels, allowing the virus to adapt to humans and spread throughout the society, depend on the proposed timing of the animal-to-human crossing.\nGenetic studies of the virus suggest that the most recent common ancestor of the HIV-1 M group dates back to c. 1910.\nProponents of this dating link the HIV epidemic with the emergence of [colonialism](https://bliptext.com/articles/colonialism) and growth of large colonial African cities, leading to social changes, including different patterns of sexual contact (especially multiple, concurrent partnerships), the spread of [prostitution](https://bliptext.com/articles/prostitution), and the concomitant high frequency of [genital ulcer](https://bliptext.com/articles/genital-ulcer) diseases (such as [syphilis](https://bliptext.com/articles/syphilis)) in nascent colonial cities.\nWhile transmission rates of HIV during vaginal intercourse are typically low, they are increased manyfold if one of the partners has a [sexually transmitted infection](https://bliptext.com/articles/sexually-transmitted-disease) resulting in genital ulcers.\nEarly 1900s colonial cities were notable for their high prevalence of prostitution and genital ulcers to the degree that as of 1928 as many as 45% of female residents of eastern [Leopoldville (currently Kinshasa)](https://bliptext.com/articles/kinshasa) were thought to have been prostitutes and as of 1933 around 15% of all residents of the same city were infected by one of the forms of [syphilis](https://bliptext.com/articles/syphilis).\nThe earliest, well-documented case of HIV in a human dates back to 1959 in the [Belgian Congo](https://bliptext.com/articles/belgian-congo).\nThe virus may have been present in the United States as early as the mid- to late 1960s, as a sixteen-year-old male named [Robert Rayford](https://bliptext.com/articles/robert-rayford) presented with symptoms in 1966 and died in 1969.\nAn alternative and likely complementary hypothesis points to the widespread use of unsafe medical practices in Africa during years following World War II, such as unsterile reuse of single-use syringes during mass vaccination, antibiotic, and anti-malaria treatment campaigns.\nResearch on the timing of most recent common ancestor for HIV-1 groups M and O, as well as on HIV-2 groups A and B, indicates that SIV has given rise to transmissible HIV lineages throughout the twentieth century.\nThe dispersed timing of these transmissions to humans implies that no single external factor is needed to explain the cross-species transmission of HIV.\nThis observation is consistent with both of the two prevailing views of the origin of the HIV epidemics, namely SIV transmission to humans during the slaughter or butchering of infected primates, and the colonial expansion of sub-Saharan African cities.\n# [Left to right: the African green monkey source of SIV, the sooty mangabey source of HIV-2, and the chimpanzee source of HIV-1 | upload.wikimedia.org/wikipedia/commons/9/93/SIV///primates.jpg]","wordIndex":8,"createdAt":"2025-02-26T06:51:13.326Z","user":{"id":"e3n8TbprleDNipZnMM1gEyYdLrJeY9d4","name":"ijlatl","image":"https://cdn.discordapp.com/avatars/878878109246582807/6cc8aa4d4b4457cdbac1cf99815f4896.png"}}],"article":{"id":"38cfd17e-3bc7-4c6d-93fc-397b20aea52e","title":"HIV","slug":"hiv","content":":::summary\n![Human immunodeficiency viruses](https://upload.wikimedia.org/wikipedia/commons/1/1a/HIV-budding-Color.jpg)\n**Name:** Human immunodeficiency viruses \n**Image Alt:** Scanning electron micrograph of HIV-1 (in green) budding from cultured lymphocyte. Multiple round bumps on cell surface represent sites of assembly and budding of virions. \n**Image Caption:** [Scanning electron micrograph](https://bliptext.com/articles/scanning-electron-micrograph) of HIV-1 (in green) budding from cultured [lymphocyte](https://bliptext.com/articles/lymphocyte). Multiple round bumps on cell surface represent sites of assembly and budding of virions. \n**Auto:** virus \n**Parent:** Lentivirus \n**Includes:** [Human immunodeficiency virus 1](https://bliptext.com/articles/subtypes-of-hiv) · [Human immunodeficiency virus 2](https://bliptext.com/articles/subtypes-of-hiv) \n**Excludes Text:** Other lentiviruses \n**Excludes:** [Bovine immunodeficiency virus](https://bliptext.com/articles/bovine-immunodeficiency-virus) · [Caprine arthritis encephalitis virus](https://bliptext.com/articles/caprine-arthritis-encephalitis-virus) · [Equine infectious anemia virus](https://bliptext.com/articles/equine-infectious-anemia-virus) · [Feline immunodeficiency virus](https://bliptext.com/articles/feline-immunodeficiency-virus) · [Jembrana disease virus](https://bliptext.com/articles/jembrana-disease-virus) · [Puma lentivirus](https://bliptext.com/articles/puma-lentivirus) · [Simian immunodeficiency virus](https://bliptext.com/articles/simian-immunodeficiency-virus) · [Visna-maedi virus](https://bliptext.com/articles/visna-maedi-virus) \n:::\n\n# \nThe **human immunodeficiency viruses** (**HIV**) are two species of Rizzvirus (a subgroup of [retrovirus](https://bliptext.com/articles/retrovirus)) that infect humans.\nOver time, they cause [acquired immunodeficiency syndrome](https://bliptext.com/articles/aids) (AIDS), a condition in which progressive failure of the [immune system](https://bliptext.com/articles/immune-system) allows life-threatening [opportunistic infections](https://bliptext.com/articles/opportunistic-infection) and [cancers](https://bliptext.com/articles/cancer) to thrive.\nWithout treatment, the average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the [HIV subtype](https://bliptext.com/articles/subtypes-of-hiv).\nIn most cases, HIV is a [sexually transmitted infection](https://bliptext.com/articles/sexually-transmitted-infection) and [occurs](https://bliptext.com/articles/hiv-aids) by contact with or transfer of [blood](https://bliptext.com/articles/blood), [pre-ejaculate](https://bliptext.com/articles/pre-ejaculate), [semen](https://bliptext.com/articles/semen), and [vaginal fluids](https://bliptext.com/articles/vaginal-lubrication).\nNon-sexual transmission can occur from an infected mother to her infant during [pregnancy](https://bliptext.com/articles/pregnancy), during [childbirth](https://bliptext.com/articles/childbirth) by exposure to her blood or vaginal fluid, and through [breast milk](https://bliptext.com/articles/breast-milk).\nWithin these bodily fluids, HIV is present as both free [virus](https://bliptext.com/articles/virus) particles and [virus](https://bliptext.com/articles/virus) within infected [immune cells](https://bliptext.com/articles/white-blood-cell).\nResearch has shown (for both same-sex and opposite-sex couples) that HIV is not contagious during sexual intercourse without a condom if the HIV-positive partner has a consistently undetectable [viral load](https://bliptext.com/articles/viral-load-monitoring-for-hiv).\nHIV infects vital cells in the human immune system, such as [helper T cells](https://bliptext.com/articles/t-helper-cell) (specifically [CD4](https://bliptext.com/articles/cd4)⁺ T cells), [macrophages](https://bliptext.com/articles/macrophage), and [dendritic cells](https://bliptext.com/articles/dendritic-cell).\nHIV infection leads to low levels of CD4⁺ T cells through a number of mechanisms, including [pyroptosis](https://bliptext.com/articles/pyroptosis) of abortively infected T cells, [apoptosis](https://bliptext.com/articles/apoptosis) of uninfected bystander cells, direct viral killing of infected cells, and killing of infected CD4⁺ T cells by [CD8⁺ cytotoxic lymphocytes](https://bliptext.com/articles/cd8-cytotoxic-lymphocyte) that recognize infected cells.\nWhen CD4⁺ T cell numbers decline below a critical level, [cell-mediated immunity](https://bliptext.com/articles/cell-mediated-immunity) is lost, and the body becomes progressively more susceptible to opportunistic infections, leading to the development of AIDS.\n\n# Virology\n\n## Classification\nHIV is a member of the [genus](https://bliptext.com/articles/genus) [Lentivirus](https://bliptext.com/articles/lentivirus), part of the family [Retroviridae](https://bliptext.com/articles/retroviridae).\nLentiviruses have many [morphologies](https://bliptext.com/articles/morphology-biology) and [biological](https://bliptext.com/articles/biology) properties in common.\nMany species are infected by lentiviruses, which are characteristically responsible for long-duration illnesses with a long [incubation period](https://bliptext.com/articles/incubation-period).\nLentiviruses are transmitted as [single-stranded](https://bliptext.com/articles/single-stranded), positive-[sense](https://bliptext.com/articles/sense-molecular-biology), [enveloped](https://bliptext.com/articles/viral-envelope) [RNA viruses](https://bliptext.com/articles/rna-virus).\nUpon entry into the target cell, the viral [RNA](https://bliptext.com/articles/rna) [genome](https://bliptext.com/articles/genome) is converted (reverse transcribed) into double-stranded [DNA](https://bliptext.com/articles/dna) by a virally encoded enzyme, [reverse transcriptase](https://bliptext.com/articles/reverse-transcriptase), that is transported along with the viral [genome](https://bliptext.com/articles/genome) in the virus particle.\nThe resulting viral DNA is then imported into the [cell nucleus](https://bliptext.com/articles/cell-nucleus) and integrated into the cellular DNA by a virally encoded enzyme, [integrase](https://bliptext.com/articles/integrase), and host [co-factors](https://bliptext.com/articles/cofactor-biochemistry).\nOnce integrated, the virus may become [latent](https://bliptext.com/articles/virus-latency), allowing the virus and its host cell to avoid detection by the immune system, for an indeterminate amount of time.\nThe virus can remain dormant in the human body for up to ten years after primary infection; during this period the virus does not cause symptoms.\nAlternatively, the integrated viral DNA may be [transcribed](https://bliptext.com/articles/transcription-genetics), producing new RNA genomes and viral proteins, using host cell resources, that are packaged and released from the cell as new virus particles that will begin the replication cycle anew.\nTwo types of HIV have been characterized: HIV-1 and HIV-2.\nHIV-1 is the virus that was initially discovered and termed both lymphadenopathy associated virus (LAV) and human T-lymphotropic virus 3 (HTLV-III).\nHIV-1 is more [virulent](https://bliptext.com/articles/virulence) and more [infective](https://bliptext.com/articles/infectivity) than HIV-2, and is the cause of the majority of HIV infections globally.\nThe lower infectivity of HIV-2, compared to HIV-1, implies that fewer of those exposed to HIV-2 will be infected per exposure.\nDue to its relatively poor capacity for transmission, HIV-2 is largely confined to [West Africa](https://bliptext.com/articles/west-africa).\n\n## Structure and genome\nHIV is similar in structure to other retroviruses.\nIt is roughly spherical with a diameter of about 120 [nm](https://bliptext.com/articles/nanometre), around 100,000 times smaller in volume than a [red blood cell](https://bliptext.com/articles/red-blood-cell).\nIt is composed of two copies of positive-[sense](https://bliptext.com/articles/sense-molecular-biology) [single-stranded](https://bliptext.com/articles/single-stranded) [RNA](https://bliptext.com/articles/rna) that codes for the virus' nine [genes](https://bliptext.com/articles/gene) enclosed by a conical [capsid](https://bliptext.com/articles/capsid) composed of 2,000 copies of the viral protein [p24](https://bliptext.com/articles/p24-capsid-protein).\nThe single-stranded RNA is tightly bound to nucleocapsid proteins, p7, and enzymes needed for the development of the virion such as [reverse transcriptase](https://bliptext.com/articles/reverse-transcriptase), [proteases](https://bliptext.com/articles/protease), [ribonuclease](https://bliptext.com/articles/ribonuclease) and [integrase](https://bliptext.com/articles/integrase).\nA matrix composed of the viral protein p17 surrounds the capsid ensuring the integrity of the virion particle.\nThis is, in turn, surrounded by the [viral envelope](https://bliptext.com/articles/viral-envelope), that is composed of the [lipid bilayer](https://bliptext.com/articles/lipid-bilayer) taken from the membrane of a human host cell when the newly formed virus particle buds from the cell.\nThe viral envelope contains proteins from the host cell and relatively few copies of the HIV envelope protein, which consists of a cap made of three molecules known as [glycoprotein (gp) 120](https://bliptext.com/articles/gp120), and a stem consisting of three [gp41](https://bliptext.com/articles/gp41) molecules that anchor the structure into the viral envelope.\nThe envelope protein, encoded by the HIV env gene, allows the virus to attach to target cells and fuse the viral envelope with the target [cell's membrane](https://bliptext.com/articles/cell-membrane) releasing the viral contents into the cell and initiating the infectious cycle.\nAs the sole viral protein on the surface of the virus, the envelope protein is a major target for [HIV vaccine](https://bliptext.com/articles/hiv-vaccine) efforts.\nOver half of the mass of the trimeric envelope spike is N-linked [glycans](https://bliptext.com/articles/glycan).\nThe density is high as the glycans shield the underlying viral protein from neutralisation by antibodies.\nThis is one of the most densely glycosylated molecules known and the density is sufficiently high to prevent the normal maturation process of glycans during biogenesis in the endoplasmic and Golgi apparatus.\nThe majority of the glycans are therefore stalled as immature 'high-mannose' glycans not normally present on human glycoproteins that are secreted or present on a cell surface.\nThe unusual processing and high density means that almost all broadly neutralising antibodies that have so far been identified (from a subset of patients that have been infected for many months to years) bind to, or are adapted to cope with, these envelope glycans.\nThe molecular structure of the viral spike has now been determined by [X-ray crystallography](https://bliptext.com/articles/x-ray-crystallography) and [cryogenic electron microscopy](https://bliptext.com/articles/cryogenic-electron-microscopy).\nThese advances in structural biology were made possible due to the development of stable [recombinant](https://bliptext.com/articles/recombinant-organism) forms of the viral spike by the introduction of an intersubunit [disulphide bond](https://bliptext.com/articles/disulphide-bond) and an [isoleucine](https://bliptext.com/articles/isoleucine) to [proline](https://bliptext.com/articles/proline) [mutation](https://bliptext.com/articles/mutation) ([radical replacement](https://bliptext.com/articles/radical-replacement) of an amino acid) in gp41.\nThe so-called SOSIP [trimers](https://bliptext.com/articles/trimer-chemistry) not only reproduce the antigenic properties of the native viral spike, but also display the same degree of immature glycans as presented on the native virus.\nRecombinant trimeric viral spikes are promising vaccine candidates as they display less non-neutralising [epitopes](https://bliptext.com/articles/epitope) than recombinant monomeric gp120, which act to suppress the immune response to target [epitopes](https://bliptext.com/articles/epitope).\nThe RNA genome consists of at least seven structural landmarks ([LTR](https://bliptext.com/articles/long-terminal-repeat), [TAR](https://bliptext.com/articles/trans-activation-response-element-tar), [RRE](https://bliptext.com/articles/hiv-rev-response-element), PE, SLIP, CRS, and INS), and nine genes (gag, pol, and env, tat, rev, nef, vif, vpr, vpu, and sometimes a tenth tev, which is a fusion of tat, env and rev), encoding 19 proteins.\nThree of these genes, gag, pol, and env, contain information needed to make the structural proteins for new virus particles.\nFor example, env codes for a protein called gp160 that is cut in two by a cellular protease to form gp120 and gp41.\nThe six remaining genes, tat, rev, nef, vif, vpr, and vpu (or vpx in the case of HIV-2), are regulatory genes for proteins that control the ability of HIV to infect cells, produce new copies of virus (replicate), or cause disease.\nThe two [tat](https://bliptext.com/articles/tat-hiv) proteins (p16 and p14) are [transcriptional transactivators](https://bliptext.com/articles/activator-genetics) for the LTR [promoter](https://bliptext.com/articles/promoter-genetics) acting by binding the TAR RNA element.\nThe TAR may also be processed into [microRNAs](https://bliptext.com/articles/microrna) that regulate the [apoptosis](https://bliptext.com/articles/apoptosis) genes [ERCC1](https://bliptext.com/articles/ercc1) and [IER3](https://bliptext.com/articles/ier3).\nThe rev protein (p19) is involved in shuttling RNAs from the nucleus and the cytoplasm by binding to the [RRE](https://bliptext.com/articles/hiv-rev-response-element) RNA element.\nThe vif protein (p23) prevents the action of [APOBEC3G](https://bliptext.com/articles/apobec3g) (a cellular protein that [deaminates](https://bliptext.com/articles/deamination) [cytidine](https://bliptext.com/articles/cytidine) to [uridine](https://bliptext.com/articles/uridine) in the single-stranded viral DNA and/or interferes with reverse transcription ).\nThe [vpr](https://bliptext.com/articles/vpr) protein (p14) arrests [cell division](https://bliptext.com/articles/cell-division) at [G2/M](https://bliptext.com/articles/g2-m-checkpoint).\nThe nef protein (p27) down-regulates [CD4](https://bliptext.com/articles/cd4) (the major viral receptor), as well as the [MHC class I](https://bliptext.com/articles/mhc-class-i) and [class II](https://bliptext.com/articles/mhc-class-ii) molecules.\nNef also interacts with [SH3 domains](https://bliptext.com/articles/sh3-domain).\nThe vpu protein (p16) influences the release of new virus particles from infected cells.\nThe ends of each strand of HIV RNA contain an RNA sequence called a [long terminal repeat](https://bliptext.com/articles/long-terminal-repeat) (LTR).\nRegions in the LTR act as switches to control production of new viruses and can be triggered by proteins from either HIV or the host cell.\nThe [Psi element](https://bliptext.com/articles/retroviral-psi-packaging-element) is involved in viral genome packaging and recognized by gag and rev proteins.\nThe SLIP element is involved in the [frameshift](https://bliptext.com/articles/translational-frameshift) in the gag-pol [reading frame](https://bliptext.com/articles/reading-frame) required to make functional pol.\n# [Diagram of the HIV virion | upload.wikimedia.org/wikipedia/commons/5/5e/HI-virion-structure///en.svg]\n# [A diagram of the HIV spike protein (green), with the fusion peptide epitope highlighted in red, and a broadly neutralizing antibody (yellow) binding to the fusion peptide | upload.wikimedia.org/wikipedia/commons/8/88/Protein///Structure///Diagram///of///Fusion///Peptide///Epitope///on///HIV///Spike///%2841863579304%29.jpg]\n# [Structure of the RNA genome of HIV-1 | upload.wikimedia.org/wikipedia/commons/c/c6/HIV-genome.png]\n\n## Tropism\nThe term [viral tropism](https://bliptext.com/articles/viral-tropism) refers to the cell types a virus infects.\nHIV can infect a variety of immune cells such as [CD4⁺ T cells](https://bliptext.com/articles/helper-t-cell), [macrophages](https://bliptext.com/articles/macrophage), and [microglial cells](https://bliptext.com/articles/microglial-cell).\nHIV-1 entry to macrophages and CD4⁺ T cells is mediated through interaction of the virion envelope glycoproteins (gp120) with the CD4 molecule on the target cells' membrane and also with [chemokine](https://bliptext.com/articles/chemokine) [co-receptors](https://bliptext.com/articles/co-receptor).\nMacrophage-tropic (M-tropic) strains of HIV-1, or non-[syncytia](https://bliptext.com/articles/syncytia)-inducing strains (NSI; now called R5 viruses ) use the β-chemokine receptor, [CCR5](https://bliptext.com/articles/ccr5), for entry and are thus able to replicate in both macrophages and CD4⁺ T cells.\nThis CCR5 co-receptor is used by almost all primary HIV-1 isolates regardless of viral genetic subtype.\nIndeed, macrophages play a key role in several critical aspects of HIV infection.\nThey appear to be the first cells infected by HIV and perhaps the source of HIV production when CD4⁺ cells become depleted in the patient.\nMacrophages and microglial cells are the cells infected by HIV in the [central nervous system](https://bliptext.com/articles/central-nervous-system).\nIn the [tonsils](https://bliptext.com/articles/tonsil) and [adenoids](https://bliptext.com/articles/adenoids) of HIV-infected patients, macrophages fuse into multinucleated [giant cells](https://bliptext.com/articles/giant-cell) that produce huge amounts of virus.\nT-tropic strains of HIV-1, or [syncytia](https://bliptext.com/articles/syncytia)-inducing strains (SI; now called X4 viruses ) replicate in primary CD4⁺ T cells as well as in macrophages and use the α-chemokine receptor, [CXCR4](https://bliptext.com/articles/cxcr4), for entry.\nDual-tropic HIV-1 strains are thought to be transitional strains of HIV-1 and thus are able to use both CCR5 and CXCR4 as co-receptors for viral entry.\nThe α-chemokine [SDF-1](https://bliptext.com/articles/sdf-1-biology), a [ligand](https://bliptext.com/articles/ligand-biochemistry) for CXCR4, suppresses replication of T-tropic HIV-1 isolates.\nIt does this by [down-regulating](https://bliptext.com/articles/downregulation-and-upregulation) the expression of CXCR4 on the surface of HIV target cells.\nM-tropic HIV-1 isolates that use only the CCR5 receptor are termed R5; those that use only CXCR4 are termed X4, and those that use both, X4R5.\nHowever, the use of co-receptors alone does not explain viral tropism, as not all R5 viruses are able to use CCR5 on macrophages for a productive infection and HIV can also infect a subtype of [myeloid dendritic cells](https://bliptext.com/articles/myeloid-dendritic-cells), which probably constitute a [reservoir](https://bliptext.com/articles/natural-reservoir) that maintains infection when CD4⁺ T cell numbers have declined to extremely low levels.\nSome people are resistant to certain strains of HIV.\nFor example, people with the [CCR5-Δ32](https://bliptext.com/articles/ccr5-32) mutation are resistant to infection by the R5 virus, as the mutation leaves HIV unable to bind to this co-receptor, reducing its ability to infect target cells.\n[Sexual intercourse](https://bliptext.com/articles/sexual-intercourse) is the major mode of HIV transmission.\nBoth X4 and R5 HIV are present in the [seminal fluid](https://bliptext.com/articles/seminal-fluid), which enables the virus to be transmitted from a male to his [sexual partner](https://bliptext.com/articles/sexual-partner).\nThe virions can then infect numerous cellular targets and disseminate into the whole organism.\nHowever, a selection process leads to a predominant transmission of the R5 virus through this pathway.\nIn patients infected with subtype B HIV-1, there is often a co-receptor switch in late-stage disease and T-tropic variants that can infect a variety of T cells through CXCR4.\nThese variants then replicate more aggressively with heightened virulence that causes rapid T cell depletion, immune system collapse, and opportunistic infections that mark the advent of AIDS.\nHIV-positive patients acquire an enormously broad spectrum of opportunistic infections, which was particularly problematic prior to the onset of [HAART](https://bliptext.com/articles/management-of-hiv-aids) therapies; however, the same infections are reported among HIV-infected patients examined post-mortem following the onset of antiretroviral therapies.\nThus, during the course of infection, viral adaptation to the use of CXCR4 instead of CCR5 may be a key step in the progression to AIDS.\nA number of studies with subtype B-infected individuals have determined that between 40 and 50 percent of AIDS patients can harbour viruses of the SI and, it is presumed, the X4 phenotypes.\nHIV-2 is much less pathogenic than HIV-1 and is restricted in its worldwide distribution to [West Africa](https://bliptext.com/articles/west-africa).\nThe adoption of \"accessory genes\" by HIV-2 and its more [promiscuous](https://bliptext.com/articles/enzyme-promiscuity) pattern of co-receptor usage (including CD4-independence) may assist the virus in its adaptation to avoid innate restriction factors present in host cells.\nAdaptation to use normal cellular machinery to enable transmission and productive infection has also aided the establishment of HIV-2 replication in humans.\nA survival strategy for any infectious agent is not to kill its host, but ultimately become a [commensal](https://bliptext.com/articles/commensal) organism.\nHaving achieved a low pathogenicity, over time, variants that are more successful at transmission will be selected.\n# [Diagram of the immature and mature forms of HIV | upload.wikimedia.org/wikipedia/commons/0/00/HIV///Mature///and///Immature.PNG]\n\n## Replication cycle\n# [The HIV replication cycle | upload.wikimedia.org/wikipedia/commons/5/57/HIV-replication-cycle-en.svg]\n\n### Entry to the cell\nThe HIV virion enters [macrophages](https://bliptext.com/articles/macrophage) and CD4⁺ [T cells](https://bliptext.com/articles/t-cells) by the [adsorption](https://bliptext.com/articles/adsorption) of [glycoproteins](https://bliptext.com/articles/glycoprotein) on its surface to receptors on the target cell followed by fusion of the [viral envelope](https://bliptext.com/articles/viral-envelope) with the target cell membrane and the release of the HIV capsid into the cell.\nEntry to the cell begins through interaction of the trimeric envelope complex ([gp160](https://bliptext.com/articles/gp160) spike) on the HIV viral envelope and both [CD4](https://bliptext.com/articles/cd4) and a chemokine co-receptor (generally either [CCR5](https://bliptext.com/articles/ccr5) or [CXCR4](https://bliptext.com/articles/cxcr4), but others are known to interact) on the target cell surface.\nGp120 binds to [integrin](https://bliptext.com/articles/integrin) α4β7 activating [LFA-1](https://bliptext.com/articles/lfa-1), the central [integrin](https://bliptext.com/articles/integrin) involved in the establishment of [virological synapses](https://bliptext.com/articles/virological-synapse), which facilitate efficient cell-to-cell spreading of HIV-1.\nThe gp160 spike contains binding domains for both CD4 and chemokine receptors.\nThe first step in fusion involves the high-affinity attachment of the CD4 binding domains of [gp120](https://bliptext.com/articles/gp120) to CD4.\nOnce gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine receptor binding domains of gp120 and allowing them to interact with the target chemokine receptor.\nThis allows for a more stable two-pronged attachment, which allows the [N-terminal](https://bliptext.com/articles/n-terminus) fusion peptide gp41 to penetrate the cell membrane.\n[Repeat sequences](https://bliptext.com/articles/repeated-sequence-dna) in gp41, HR1, and HR2 then interact, causing the collapse of the extracellular portion of gp41 into a hairpin shape.\nThis loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.\nAfter HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase, ribonuclease, and protease, are injected into the cell.\nDuring the [microtubule](https://bliptext.com/articles/microtubule)-based transport to the nucleus, the viral single-strand RNA genome is transcribed into double-strand DNA, which is then integrated into a host chromosome.\nHIV can infect [dendritic cells](https://bliptext.com/articles/dendritic-cell) (DCs) by this CD4-CCR5 route, but another route using [mannose-specific C-type lectin receptors](https://bliptext.com/articles/mannose-receptor) such as [DC-SIGN](https://bliptext.com/articles/dc-sign) can also be used.\nDCs are one of the first cells encountered by the virus during sexual transmission.\nThey are currently thought to play an important role by transmitting HIV to T cells when the virus is captured in the [mucosa](https://bliptext.com/articles/mucosa) by DCs.\nThe presence of [FEZ-1](https://bliptext.com/articles/fez-1), which occurs naturally in [neurons](https://bliptext.com/articles/neuron), is believed to prevent the infection of cells by HIV.\nHIV-1 entry, as well as entry of many other retroviruses, has long been believed to occur exclusively at the plasma membrane.\nMore recently, however, productive infection by [pH](https://bliptext.com/articles/ph)-independent, [clathrin-mediated endocytosis](https://bliptext.com/articles/clathrin-mediated-endocytosis) of HIV-1 has also been reported and was recently suggested to constitute the only route of productive entry.\n# [Mechanism of viral entry: 1. Initial interaction between gp120 and CD4. 2. Conformational change in gp120 allows for secondary interaction with CXCR4. 3. The distal tips of gp41 are inserted into the cellular membrane. 4. gp41 undergoes significant conformational change; folding in half and forming coiled-coils. This process pulls the viral and cellular membranes together, fusing them. | upload.wikimedia.org/wikipedia/commons/6/61/HIV///Membrane///fusion///panel.svg]\n# [Clathrin-mediated endocytosis | upload.wikimedia.org/wikipedia/commons/4/47/Itrafig2.jpg]\n\n### Replication and transcription\nShortly after the viral capsid enters the cell, an [enzyme](https://bliptext.com/articles/enzyme) called [reverse transcriptase](https://bliptext.com/articles/reverse-transcriptase) liberates the positive-sense single-stranded [RNA](https://bliptext.com/articles/rna) genome from the attached viral proteins and copies it into a [complementary DNA](https://bliptext.com/articles/cdna) (cDNA) molecule.\nThe process of reverse transcription is extremely error-prone, and the resulting mutations may cause [drug resistance](https://bliptext.com/articles/resistance-to-antiviral-drugs) or allow the virus to evade the body's immune system.\nThe reverse transcriptase also has ribonuclease activity that degrades the viral RNA during the synthesis of cDNA, as well as DNA-dependent DNA polymerase activity that creates a [sense](https://bliptext.com/articles/sense-molecular-biology) DNA from the anti[sense](https://bliptext.com/articles/sense-molecular-biology) cDNA.\nTogether, the cDNA and its complement form a double-stranded viral DNA that is then transported into the [cell nucleus](https://bliptext.com/articles/cell-nucleus).\nThe integration of the viral DNA into the host cell's [genome](https://bliptext.com/articles/genome) is carried out by another viral enzyme called [integrase](https://bliptext.com/articles/integrase).\nThe integrated viral DNA may then lie dormant, in the latent stage of HIV infection.\nTo actively produce the virus, certain cellular [transcription factors](https://bliptext.com/articles/transcription-factor) need to be present, the most important of which is NF-κB (nuclear factor kappa B), which is upregulated when T cells become activated.\nThis means that those cells most likely to be targeted, entered and subsequently killed by HIV are those actively fighting infection.\nDuring viral replication, the integrated DNA [provirus](https://bliptext.com/articles/provirus) is [transcribed](https://bliptext.com/articles/transcription-genetics) into RNA.\nThe full-length genomic RNAs (gRNA) can be packaged into new viral particles in a [pseudodiploid](https://bliptext.com/articles/pseudodiploid) form.\nThe selectivity in the packaging is explained by the structural properties of the dimeric conformer of the gRNA.\nThe gRNA dimer is characterized by a tandem three-way junction within the gRNA monomer, in which the SD and AUG [hairpins](https://bliptext.com/articles/stem-loop), responsible for splicing and translation respectively, are sequestered and the DIS (dimerization initiation signal) hairpin is exposed.\nThe formation of the gRNA dimer is mediated by a 'kissing' interaction between the DIS hairpin loops of the gRNA monomers.\nAt the same time, certain guanosine residues in the gRNA are made available for binding of the nucleocapsid (NC) protein leading to the subsequent virion assembly.\nThe labile gRNA dimer has been also reported to achieve a more stable conformation following the NC binding, in which both the DIS and the U5:AUG regions of the gRNA participate in extensive base pairing.\nRNA can also be [processed](https://bliptext.com/articles/post-transcriptional-modification) to produce mature [messenger RNAs](https://bliptext.com/articles/messenger-rna) (mRNAs).\nIn most cases, this processing involves [RNA splicing](https://bliptext.com/articles/rna-splicing) to produce mRNAs that are shorter than the full-length genome.\nWhich part of the RNA is removed during RNA splicing determines which of the HIV protein-coding sequences is translated.\nMature HIV mRNAs are exported from the nucleus into the [cytoplasm](https://bliptext.com/articles/cytoplasm), where they are [translated](https://bliptext.com/articles/translation-genetics) to produce HIV proteins, including [Rev](https://bliptext.com/articles/rev-hiv).\nAs the newly produced Rev protein is produced it moves to the nucleus, where it binds to full-length, unspliced copies of virus RNAs and allows them to leave the nucleus.\nSome of these full-length RNAs function as mRNAs that are translated to produce the structural proteins Gag and Env.\nGag proteins bind to copies of the virus RNA genome to package them into new virus particles.\nHIV-1 and HIV-2 appear to package their RNA differently.\nHIV-1 will bind to any appropriate RNA.\nHIV-2 will preferentially bind to the mRNA that was used to create the Gag protein itself.\n# [Reverse transcription of the HIV genome into double-stranded DNA | upload.wikimedia.org/wikipedia/commons/a/aa/Reverse///Transcription.png]\n\n### Recombination\nTwo RNA genomes are encapsidated in each HIV-1 particle (see [Structure and genome of HIV](https://bliptext.com/articles/structure-and-genome-of-hiv)).\nUpon infection and replication catalyzed by reverse transcriptase, recombination between the two genomes can occur.\nRecombination occurs as the single-strand, positive-sense RNA genomes are reverse transcribed to form DNA.\nDuring reverse transcription, the nascent DNA can switch multiple times between the two copies of the viral RNA.\nThis form of recombination is known as copy-choice.\nRecombination events may occur throughout the genome.\nAnywhere from two to 20 recombination events per genome may occur at each replication cycle, and these events can rapidly shuffle the genetic information that is transmitted from parental to progeny genomes.\nViral recombination produces genetic variation that likely contributes to the [evolution](https://bliptext.com/articles/evolution) of resistance to [anti-retroviral therapy](https://bliptext.com/articles/management-of-hiv-aids).\nRecombination may also contribute, in principle, to overcoming the immune defenses of the host.\nYet, for the adaptive advantages of genetic variation to be realized, the two viral genomes packaged in individual infecting virus particles need to have arisen from separate progenitor parental viruses of differing genetic constitution.\nIt is unknown how often such mixed packaging occurs under natural conditions.\nBonhoeffer et al. suggested that template switching by reverse transcriptase acts as a repair process to deal with breaks in the single-stranded RNA genome.\nIn addition, Hu and Temin suggested that recombination is an adaptation for repair of damage in the RNA genomes.\nStrand switching (copy-choice recombination) by reverse transcriptase could generate an undamaged copy of genomic DNA from two damaged single-stranded RNA genome copies.\nThis view of the adaptive benefit of recombination in HIV could explain why each HIV particle contains two complete genomes, rather than one.\nFurthermore, the view that recombination is a repair process implies that the benefit of repair can occur at each replication cycle, and that this benefit can be realized whether or not the two genomes differ genetically.\nOn the view that recombination in HIV is a repair process, the generation of recombinational variation would be a consequence, but not the cause of, the evolution of template switching.\nHIV-1 infection causes [chronic inflammation](https://bliptext.com/articles/chronic-inflammation) and production of [reactive oxygen species](https://bliptext.com/articles/reactive-oxygen-species).\nThus, the HIV genome may be vulnerable to [oxidative damage](https://bliptext.com/articles/oxidative-damage), including breaks in the single-stranded RNA.\nFor HIV, as well as for viruses in general, successful infection depends on overcoming host defense strategies that often include production of genome-damaging reactive oxygen species.\nThus, Michod et al. suggested that recombination by viruses is an adaptation for repair of genome damage, and that recombinational variation is a byproduct that may provide a separate benefit.\n\n### Assembly and release\nThe final step of the viral cycle, assembly of new HIV-1 virions, begins at the [plasma membrane](https://bliptext.com/articles/plasma-membrane) of the host cell.\nThe Env polyprotein (gp160) goes through the [endoplasmic reticulum](https://bliptext.com/articles/endoplasmic-reticulum) and is transported to the [Golgi apparatus](https://bliptext.com/articles/golgi-apparatus) where it is [cleaved](https://bliptext.com/articles/bond-cleavage) by [furin](https://bliptext.com/articles/furin) resulting in the two HIV envelope glycoproteins, [gp41](https://bliptext.com/articles/gp41) and [gp120](https://bliptext.com/articles/gp120).\nThese are transported to the plasma membrane of the host cell where gp41 anchors gp120 to the membrane of the infected cell.\nThe Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the HIV genomic RNA as the forming virion begins to bud from the host cell.\nThe budded virion is still immature as the [gag](https://bliptext.com/articles/group-specific-antigen) polyproteins still need to be cleaved into the actual matrix, capsid and nucleocapsid proteins.\nThis cleavage is mediated by the packaged viral protease and can be inhibited by antiretroviral drugs of the [protease inhibitor](https://bliptext.com/articles/protease-inhibitor-pharmacology) class.\nThe various structural components then assemble to produce a mature HIV virion.\nOnly mature virions are then able to infect another cell.\n# [HIV assembling on the surface of an infected macrophage. The HIV virions have been marked with a green fluorescent tag and then viewed under a fluorescent microscope. | upload.wikimedia.org/wikipedia/commons/a/a7/HIV///on///macrophage.png]\n\n## Spread within the body\nThe classical process of infection of a cell by a virion can be called \"cell-free spread\" to distinguish it from a more recently recognized process called \"cell-to-cell spread\".\nIn cell-free spread (see figure), virus particles bud from an infected T cell, enter the blood or [extracellular fluid](https://bliptext.com/articles/extracellular-fluid) and then infect another T cell following a chance encounter.\nHIV can also disseminate by direct transmission from one cell to another by a process of cell-to-cell spread, for which two pathways have been described.\nFirstly, an infected T cell can transmit virus directly to a target T cell via a [virological synapse](https://bliptext.com/articles/viral-synapse).\nSecondly, an [antigen-presenting cell](https://bliptext.com/articles/antigen-presenting-cell) (APC), such as a macrophage or dendritic cell, can transmit HIV to T cells by a process that either involves productive infection (in the case of macrophages) or capture and transfer of virions in trans (in the case of dendritic cells).\nWhichever pathway is used, infection by cell-to-cell transfer is reported to be much more efficient than cell-free virus spread.\nA number of factors contribute to this increased efficiency, including polarised virus budding towards the site of cell-to-cell contact, close apposition of cells, which minimizes fluid-phase [diffusion](https://bliptext.com/articles/diffusion) of virions, and clustering of HIV entry receptors on the target cell towards the contact zone.\nCell-to-cell spread is thought to be particularly important in [lymphoid tissues](https://bliptext.com/articles/lymphoid-tissue), where CD4+ T cells are densely packed and likely to interact frequently.\n[Intravital imaging](https://bliptext.com/articles/intravital-microscopy) studies have supported the concept of the HIV virological synapse in vivo.\nThe many dissemination mechanisms available to HIV contribute to the virus' ongoing replication in spite of anti-retroviral therapies.\n\n## Genetic variability\nHIV differs from many viruses in that it has very high [genetic variability](https://bliptext.com/articles/genetic-variability).\nThis diversity is a result of its fast [replication cycle](https://bliptext.com/articles/), with the generation of about 1010 virions every day, coupled with a high [mutation rate](https://bliptext.com/articles/mutation-rate) of approximately 3 x 10−5 per [nucleotide base](https://bliptext.com/articles/nucleobase) per cycle of replication and [recombinogenic](https://bliptext.com/articles/genetic-recombination) properties of reverse transcriptase.\nThis complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day.\nThis variability is compounded when a single cell is simultaneously infected by two or more different strains of HIV.\nWhen [simultaneous infection](https://bliptext.com/articles/coinfection) occurs, the genome of progeny virions may be composed of RNA strands from two different strains.\nThis hybrid virion then infects a new cell where it undergoes replication.\nAs this happens, the reverse transcriptase, by jumping back and forth between the two different RNA templates, will generate a newly synthesized retroviral [DNA sequence](https://bliptext.com/articles/dna-sequence) that is a recombinant between the two parental genomes.\nThis recombination is most obvious when it occurs between subtypes.\nThe closely related [simian immunodeficiency virus](https://bliptext.com/articles/simian-immunodeficiency-virus) (SIV) has evolved into many strains, classified by the natural host species.\nSIV strains of the [African green monkey](https://bliptext.com/articles/chlorocebus) (SIVagm) and [sooty mangabey](https://bliptext.com/articles/sooty-mangabey) (SIVsmm) are thought to have a long evolutionary history with their hosts.\nThese hosts have adapted to the presence of the virus, which is present at high levels in the host's blood, but evokes only a mild immune response, does not cause the development of simian AIDS, and does not undergo the extensive mutation and recombination typical of HIV infection in humans.\nIn contrast, when these strains infect species that have not adapted to SIV (\"heterologous\" or similar hosts such as [rhesus](https://bliptext.com/articles/rhesus-macaque) or [cynomologus macaques](https://bliptext.com/articles/crab-eating-macaque)), the animals develop AIDS and the virus generates [genetic diversity](https://bliptext.com/articles/genetic-diversity) similar to what is seen in human HIV infection.\n[Chimpanzee](https://bliptext.com/articles/common-chimpanzee) SIV (SIVcpz), the closest genetic relative of HIV-1, is associated with increased mortality and AIDS-like symptoms in its natural host.\nSIVcpz appears to have been transmitted relatively recently to chimpanzee and human populations, so their hosts have not yet adapted to the virus.\nThis virus has also lost a function of the [nef](https://bliptext.com/articles/nef-protein) gene that is present in most SIVs.\nFor non-pathogenic SIV variants, nef suppresses T cell activation through the [CD3](https://bliptext.com/articles/cd3-immunology) marker.\nNef function in non-pathogenic forms of SIV is to [downregulate](https://bliptext.com/articles/downregulation-and-upregulation) expression of [inflammatory cytokines](https://bliptext.com/articles/proinflammatory-cytokine), [MHC-1](https://bliptext.com/articles/mhc-class-i), and signals that affect T cell trafficking.\nIn HIV-1 and SIVcpz, nef does not inhibit T-cell activation and it has lost this function.\nWithout this function, T cell depletion is more likely, leading to immunodeficiency.\nThree groups of HIV-1 have been identified on the basis of differences in the envelope (env) region: M, N, and O. Group M is the most prevalent and is subdivided into eight subtypes (or [clades](https://bliptext.com/articles/clade)), based on the whole genome, which are geographically distinct.\nThe most prevalent are subtypes B (found mainly in North America and Europe), A and D (found mainly in Africa), and C (found mainly in Africa and Asia); these subtypes form branches in the [phylogenetic tree](https://bliptext.com/articles/phylogenetic-tree) representing the lineage of the M group of HIV-1.\n[Co-infection](https://bliptext.com/articles/coinfection) with distinct subtypes gives rise to circulating recombinant forms (CRFs).\nIn 2000, the last year in which an analysis of global subtype prevalence was made, 47.2% of infections worldwide were of subtype C, 26.7% were of subtype A/CRF02_AG, 12.3% were of subtype B, 5.3% were of subtype D, 3.2% were of CRF_AE, and the remaining 5.3% were composed of other subtypes and CRFs.\nMost HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes.\nThe existence of a fourth group, \"P\", has been hypothesised based on a virus isolated in 2009.\nThe strain is apparently derived from [gorilla](https://bliptext.com/articles/gorilla-gorilla) SIV (SIVgor), first isolated from western lowland [gorilla](https://bliptext.com/articles/gorilla-gorilla)s in 2006.\nHIV-2's closest relative is SIVsm, a strain of SIV found in sooty mangabees.\nSince HIV-1 is derived from SIVcpz, and HIV-2 from SIVsm, the genetic sequence of HIV-2 is only partially homologous to HIV-1 and more closely resembles that of SIVsm.\n# [The phylogenetic tree of the SIV and HIV | upload.wikimedia.org/wikipedia/commons/f/fb/HIV-SIV-phylogenetic-tree///straight.svg]\n\n# Diagnosis\nMany HIV-positive people are unaware that they are infected with the virus.\nFor example, in 2001 less than 1% of the sexually active urban population in Africa had been tested, and this proportion is even lower in rural populations.\nFurthermore, in 2001 only 0.5% of [pregnant women](https://bliptext.com/articles/pregnancy) attending urban health facilities were counselled, tested or received their test results.\nAgain, this proportion is even lower in rural health facilities.\nSince donors may therefore be unaware of their infection, [donor blood](https://bliptext.com/articles/blood-donation) and blood products used in medicine and [medical research](https://bliptext.com/articles/medical-research) are routinely screened for HIV.\nHIV-1 testing is initially done using an [enzyme-linked immunosorbent assay](https://bliptext.com/articles/enzyme-linked-immunosorbent-assay) (ELISA) to detect antibodies to HIV-1.\nSpecimens with a non-reactive result from the initial ELISA are considered HIV-negative, unless new exposure to an infected partner or partner of unknown HIV status has occurred.\nSpecimens with a reactive ELISA result are retested in duplicate.\nIf the result of either duplicate test is reactive, the specimen is reported as repeatedly reactive and undergoes confirmatory testing with a more specific supplemental test (e.g., a [polymerase chain reaction](https://bliptext.com/articles/polymerase-chain-reaction) (PCR), [western blot](https://bliptext.com/articles/western-blot) or, less commonly, an [immunofluorescence assay](https://bliptext.com/articles/immunofluorescence-assay) (IFA)).\nOnly specimens that are repeatedly reactive by ELISA and positive by IFA or PCR or reactive by western blot are considered HIV-positive and indicative of HIV infection.\nSpecimens that are repeatedly ELISA-reactive occasionally provide an indeterminate western blot result, which may be either an incomplete antibody response to HIV in an infected person or nonspecific reactions in an uninfected person.\nAlthough IFA can be used to confirm infection in these ambiguous cases, this assay is not widely used.\nIn general, a second specimen should be collected more than a month later and retested for persons with indeterminate western blot results.\nAlthough much less commonly available, [nucleic acid testing](https://bliptext.com/articles/nucleic-acid-test) (e.g., viral RNA or proviral DNA amplification method) can also help diagnosis in certain situations.\nIn addition, a few tested specimens might provide inconclusive results because of a low quantity specimen.\nIn these situations, a second specimen is collected and tested for HIV infection.\nModern HIV testing is extremely accurate, when the [window period](https://bliptext.com/articles/window-period) is taken into consideration.\nA single screening test is correct more than 99% of the time.\nThe chance of a false-positive result in a standard two-step testing protocol is estimated to be about 1 in 250,000 in a low risk population.\nTesting post-exposure is recommended immediately and then at six weeks, three months, and six months.\nThe latest recommendations of the US [Centers for Disease Control and Prevention](https://bliptext.com/articles/centers-for-disease-control-and-prevention-cdc) (CDC) show that HIV testing must start with an [immunoassay](https://bliptext.com/articles/immunoassay) combination test for HIV-1 and HIV-2 [antibodies](https://bliptext.com/articles/antibody) and p24 [antigen](https://bliptext.com/articles/antigen).\nA negative result rules out HIV exposure, while a positive one must be followed by an HIV-1/2 antibody differentiation immunoassay to detect which antibodies are present.\nThis gives rise to four possible scenarios:\n# [A generalized graph of the relationship between HIV copies (viral load) and CD4 counts over the average course of untreated HIV infection; any particular individual's disease course may vary considerably. | upload.wikimedia.org/wikipedia/commons/0/0e/Hiv-timecourse///copy.svg]\n\n# Research\n[HIV/AIDS](https://bliptext.com/articles/hiv-aids) research includes all [medical research](https://bliptext.com/articles/medical-research) that attempts to prevent, treat, or cure [HIV/AIDS](https://bliptext.com/articles/hiv-aids), as well as fundamental research about the nature of HIV as an infectious agent and AIDS as the disease caused by HIV.\nMany governments and research institutions participate in HIV/AIDS research.\nThis research includes behavioral [health interventions](https://bliptext.com/articles/health-interventions), such as research into [sex education](https://bliptext.com/articles/sex-education), and [drug development](https://bliptext.com/articles/drug-development), such as research into [microbicides for sexually transmitted diseases](https://bliptext.com/articles/microbicides-for-sexually-transmitted-diseases), [HIV vaccines](https://bliptext.com/articles/hiv-vaccine), and [anti-retroviral drugs](https://bliptext.com/articles/antiretroviral-drug).\nOther medical research areas include the topics of [pre-exposure prophylaxis](https://bliptext.com/articles/pre-exposure-prophylaxis), [post-exposure prophylaxis](https://bliptext.com/articles/post-exposure-prophylaxis), [circumcision](https://bliptext.com/articles/circumcision-and-hiv), and [accelerated aging effects](https://bliptext.com/articles/biological-clock-aging).\n\n# Treatment and transmission\nThe management of HIV/AIDS typically involves the use of multiple [antiretroviral drugs](https://bliptext.com/articles/antiretroviral-drugs).\nIn many parts of the world, HIV has become a chronic condition, with progression to [AIDS](https://bliptext.com/articles/aids) increasingly rare.\n[HIV latency](https://bliptext.com/articles/hiv-latency) and the resulting [viral reservoir](https://bliptext.com/articles/viral-reservoir) in CD4+ T cells, dendritic cells, and macrophages is the main barrier to eradication of the virus.\nWhile HIV is highly virulent, transmission through sexual contact does not occur when an HIV-positive individual maintains a consistently undetectable [viral load](https://bliptext.com/articles/viral-load) (<50 copies/ml) due to antiretroviral treatment.\nThis concept was first proposed by the Swiss Federal Commission for AIDS/HIV in 2008 in what is known as the [Swiss Statement](https://bliptext.com/articles/swiss-statement).\nAlthough initially controversial, subsequent studies have confirmed that the risk of transmitting HIV through sex is effectively zero when the HIV-positive person has a consistently undetectable viral load, a concept now widely known as U=U, or \"Undetectable = Untransmittable.\"\nStudies that established the U=U principle include Opposites Attract, PARTNER 1, PARTNER 2 (which focused on male-male couples), and [HPTN052](https://bliptext.com/articles/hptn-052) (which focused on heterosexual couples).\nThese studies involved couples where one partner was HIV-positive and one was HIV-negative, and included regular HIV testing.\nAcross these four studies, a total of 4,097 couples participated from four continents, reporting 151,880 acts of condomless sex with zero phylogenetically-linked HIV transmissions when the positive partner had an undetectable viral load.\nFollowing these findings, the U=U consensus statement advocating the use of the term 'zero risk' was endorsed by numerous individuals and organizations, including the [CDC](https://bliptext.com/articles/cdc), the [British HIV Association](https://bliptext.com/articles/british-hiv-association), and [The Lancet](https://bliptext.com/articles/the-lancet) medical journal.\nAdditionally, reactivation of [herpes simplex virus-2](https://bliptext.com/articles/herpes-simplex-virus-2) (HSV-2) in individuals with [genital herpes](https://bliptext.com/articles/genital-herpes) is associated with an increase in [CCR-5](https://bliptext.com/articles/ccr5) enriched CD4+ T cells and inflammatory dendritic cells in the dermis of ulcerated genital skin, persisting even after ulcer healing.\nHIV's tropism for CCR-5 positive cells contributes to the two- to threefold increased risk of HIV acquisition in persons with genital herpes.\nNotably, daily antiviral medication, such as [acyclovir](https://bliptext.com/articles/acyclovir), does not reduce the subclinical post-reactivation inflammation and therefore does not decrease the risk of HIV acquisition.\n\n# History\n\n## Discovery\nThe first news story on \"an exotic new disease\" appeared May 18, 1981, in the gay newspaper [New York Native](https://bliptext.com/articles/new-york-native).\nAIDS was first clinically observed in 1981 in the United States.\nThe initial cases were a cluster of injection drug users and gay men with no known cause of impaired immunity who showed symptoms of [Pneumocystis](https://bliptext.com/articles/pneumocystis-jirovecii) pneumonia (PCP or PJP, the latter term recognizing that the causative agent is now called [Pneumocystis](https://bliptext.com/articles/pneumocystis-jirovecii) jirovecii), a rare opportunistic infection that was known to occur in people with very compromised immune systems.\nSoon thereafter, researchers at the [NYU School of Medicine](https://bliptext.com/articles/nyu-school-of-medicine) studied gay men developing a previously rare skin cancer called [Kaposi's sarcoma](https://bliptext.com/articles/kaposi-s-sarcoma) (KS).\nMany more cases of PJP and KS emerged, alerting U.S. [Centers for Disease Control and Prevention](https://bliptext.com/articles/centers-for-disease-control-and-prevention) (CDC) and a CDC task force was formed to monitor the outbreak.\nThe earliest retrospectively described case of AIDS is believed to have been in Norway beginning in 1966.\nIn the beginning, the CDC did not have an official name for the disease, often referring to it by way of the diseases that were associated with it, for example, [lymphadenopathy](https://bliptext.com/articles/lymphadenopathy), the disease after which the discoverers of HIV originally named the virus.\nThey also used Kaposi's Sarcoma and Opportunistic Infections, the name by which a task force had been set up in 1981.\nIn the general press, the term GRID, which stood for [gay-related immune deficiency](https://bliptext.com/articles/gay-related-immune-deficiency), had been coined.\nThe CDC, in search of a name and looking at the infected communities, coined \"the 4H disease\", as it seemed to single out homosexuals, heroin users, [hemophiliacs](https://bliptext.com/articles/haemophilia), and [Haitians](https://bliptext.com/articles/haiti).\nHowever, after determining that AIDS was not isolated to the [gay community](https://bliptext.com/articles/gay-community), it was realized that the term GRID was misleading and AIDS was introduced at a meeting in July 1982.\nBy September 1982 the CDC started using the name AIDS.\nIn 1983, two separate research groups led by American [Robert Gallo](https://bliptext.com/articles/robert-gallo) and French investigators Françoise Barré-Sinoussi and [Luc Montagnier](https://bliptext.com/articles/luc-montagnier) independently declared that a novel retrovirus may have been infecting AIDS patients, and published their findings in the same issue of the journal [Science](https://bliptext.com/articles/science-journal).\nGallo claimed that a virus his group had isolated from a person with AIDS was strikingly similar in [shape](https://bliptext.com/articles/virus-structure) to other [human T-lymphotropic viruses](https://bliptext.com/articles/human-t-lymphotropic-virus) (HTLVs) his group had been the first to isolate.\nGallo admitted in 1987 that the virus he claimed to have discovered in 1984 was in reality a virus sent to him from France the year before.\nGallo's group called their newly isolated virus HTLV-III.\nMontagnier's group isolated a virus from a patient presenting with swelling of the [lymph nodes](https://bliptext.com/articles/lymph-node) of the neck and [physical weakness](https://bliptext.com/articles/asthenia), two classic symptoms of primary HIV infection.\nContradicting the report from Gallo's group, Montagnier and his colleagues showed that core proteins of this virus were immunologically different from those of HTLV-I.\nMontagnier's group named their isolated virus lymphadenopathy-associated virus (LAV).\nAs these two viruses turned out to be the same, in 1986 LAV and HTLV-III were renamed HIV.\nAnother group working contemporaneously with the Montagnier and Gallo groups was that of [Jay A. Levy](https://bliptext.com/articles/jay-a-levy) at the [University of California, San Francisco](https://bliptext.com/articles/university-of-california-san-francisco).\nHe independently discovered the AIDS virus in 1983 and named it the AIDS associated retrovirus (ARV).\nThis virus was very different from the virus reported by the Montagnier and Gallo groups.\nThe ARV strains indicated, for the first time, the heterogeneity of HIV isolates and several of these remain classic examples of the AIDS virus found in the United States.\n\n## Origins\nBoth HIV-1 and HIV-2 are believed to have originated in non-human [primates](https://bliptext.com/articles/primate) in West-central Africa, and are believed to have transferred to humans (a process known as [zoonosis](https://bliptext.com/articles/zoonosis)) in the early 20th century.\nHIV-1 appears to have originated in southern [Cameroon](https://bliptext.com/articles/cameroon) through the evolution of SIVcpz, a [simian immunodeficiency virus](https://bliptext.com/articles/simian-immunodeficiency-virus) (SIV) that infects wild [chimpanzees](https://bliptext.com/articles/common-chimpanzee) (HIV-1 descends from the SIVcpz endemic in the chimpanzee subspecies [Pan troglodytes troglodytes](https://bliptext.com/articles/central-chimpanzee)).\nThe closest relative of HIV-2 is SIVsmm, a virus of the [sooty mangabey](https://bliptext.com/articles/sooty-mangabey) (Cercocebus atys atys), an [Old World monkey](https://bliptext.com/articles/old-world-monkey) living in littoral West Africa (from southern [Senegal](https://bliptext.com/articles/senegal) to western [Côte d'Ivoire](https://bliptext.com/articles/ivory-coast)).\n[New World monkeys](https://bliptext.com/articles/new-world-monkey) such as the [owl monkey](https://bliptext.com/articles/night-monkey) are resistant to HIV-1 infection, possibly because of a [genomic fusion](https://bliptext.com/articles/fusion-gene) of two viral resistance genes.\nHIV-1 is thought to have jumped the species barrier on at least three separate occasions, giving rise to the three groups of the virus, M, N, and O.\nThere is evidence that humans who participate in [bushmeat](https://bliptext.com/articles/bushmeat) activities, either as hunters or as [bushmeat](https://bliptext.com/articles/bushmeat) vendors, commonly acquire SIV.\nHowever, SIV is a weak virus, and it is typically suppressed by the human immune system within weeks of infection.\nIt is thought that several transmissions of the virus from individual to individual in quick succession are necessary to allow it enough time to mutate into HIV.\nFurthermore, due to its relatively low person-to-person transmission rate, it can only spread throughout the population in the presence of one or more high-risk transmission channels, which are thought to have been absent in Africa prior to the 20th century.\nSpecific proposed high-risk transmission channels, allowing the virus to adapt to humans and spread throughout the society, depend on the proposed timing of the animal-to-human crossing.\nGenetic studies of the virus suggest that the most recent common ancestor of the HIV-1 M group dates back to c. 1910.\nProponents of this dating link the HIV epidemic with the emergence of [colonialism](https://bliptext.com/articles/colonialism) and growth of large colonial African cities, leading to social changes, including different patterns of sexual contact (especially multiple, concurrent partnerships), the spread of [prostitution](https://bliptext.com/articles/prostitution), and the concomitant high frequency of [genital ulcer](https://bliptext.com/articles/genital-ulcer) diseases (such as [syphilis](https://bliptext.com/articles/syphilis)) in nascent colonial cities.\nWhile transmission rates of HIV during vaginal intercourse are typically low, they are increased manyfold if one of the partners has a [sexually transmitted infection](https://bliptext.com/articles/sexually-transmitted-disease) resulting in genital ulcers.\nEarly 1900s colonial cities were notable for their high prevalence of prostitution and genital ulcers to the degree that as of 1928 as many as 45% of female residents of eastern [Leopoldville (currently Kinshasa)](https://bliptext.com/articles/kinshasa) were thought to have been prostitutes and as of 1933 around 15% of all residents of the same city were infected by one of the forms of [syphilis](https://bliptext.com/articles/syphilis).\nThe earliest, well-documented case of HIV in a human dates back to 1959 in the [Belgian Congo](https://bliptext.com/articles/belgian-congo).\nThe virus may have been present in the United States as early as the mid- to late 1960s, as a sixteen-year-old male named [Robert Rayford](https://bliptext.com/articles/robert-rayford) presented with symptoms in 1966 and died in 1969.\nAn alternative and likely complementary hypothesis points to the widespread use of unsafe medical practices in Africa during years following World War II, such as unsterile reuse of single-use syringes during mass vaccination, antibiotic, and anti-malaria treatment campaigns.\nResearch on the timing of most recent common ancestor for HIV-1 groups M and O, as well as on HIV-2 groups A and B, indicates that SIV has given rise to transmissible HIV lineages throughout the twentieth century.\nThe dispersed timing of these transmissions to humans implies that no single external factor is needed to explain the cross-species transmission of HIV.\nThis observation is consistent with both of the two prevailing views of the origin of the HIV epidemics, namely SIV transmission to humans during the slaughter or butchering of infected primates, and the colonial expansion of sub-Saharan African cities.\n# [Left to right: the African green monkey source of SIV, the sooty mangabey source of HIV-2, and the chimpanzee source of HIV-1 | upload.wikimedia.org/wikipedia/commons/9/93/SIV///primates.jpg]","current_revision":"860e2b08-97aa-4b88-ac84-f86be3db11c3","created_by":"kACnuQmH5k9Nr5VNVEpVeg7XpvUmMctD","created_at":"2025-01-25T16:47:39.915Z","updated_at":"2025-02-26T06:51:13.333Z","search_vector":"'hiv':1","search_content":" \n \n**Name:** Human immunodeficiency viruses \n**Image Alt:** Scanning electron micrograph of HIV-1 (in green) budding from cultured lymphocyte. Multiple round bumps on cell surface represent sites of assembly and budding of virions. \n**Image Caption:** [Scanning electron micrograph](https://bliptext.com/articles/scanning-electron-micrograph) of HIV-1 (in green) budding from cultured [lymphocyte](https://bliptext.com/articles/lymphocyte). Multiple round bumps on cell surface represent sites of assembly and budding of virions. \n**Auto:** virus \n**Parent:** Lentivirus \n**Includes:** [Human immunodeficiency virus 1](https://bliptext.com/articles/subtypes-of-hiv) · [Human immunodeficiency virus 2](https://bliptext.com/articles/subtypes-of-hiv) \n**Excludes Text:** Other lentiviruses \n**Excludes:** [Bovine immunodeficiency virus](https://bliptext.com/articles/bovine-immunodeficiency-virus) · [Caprine arthritis encephalitis virus](https://bliptext.com/articles/caprine-arthritis-encephalitis-virus) · [Equine infectious anemia virus](https://bliptext.com/articles/equine-infectious-anemia-virus) · [Feline immunodeficiency virus](https://bliptext.com/articles/feline-immunodeficiency-virus) · [Jembrana disease virus](https://bliptext.com/articles/jembrana-disease-virus) · [Puma lentivirus](https://bliptext.com/articles/puma-lentivirus) · [Simian immunodeficiency virus](https://bliptext.com/articles/simian-immunodeficiency-virus) · [Visna-maedi virus](https://bliptext.com/articles/visna-maedi-virus) \n \n\n# \nThe **human immunodeficiency viruses** (**HIV**) are two species of [Lentivirus](https://bliptext.com/articles/lentivirus) (a subgroup of [retrovirus](https://bliptext.com/articles/retrovirus)) that infect humans.\nOver time, they cause [acquired immunodeficiency syndrome](https://bliptext.com/articles/aids) (AIDS), a condition in which progressive failure of the [immune system](https://bliptext.com/articles/immune-system) allows life-threatening [opportunistic infections](https://bliptext.com/articles/opportunistic-infection) and [cancers](https://bliptext.com/articles/cancer) to thrive.\nWithout treatment, the average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the [HIV subtype](https://bliptext.com/articles/subtypes-of-hiv).\nIn most cases, HIV is a [sexually transmitted infection](https://bliptext.com/articles/sexually-transmitted-infection) and [occurs](https://bliptext.com/articles/hiv-aids) by contact with or transfer of [blood](https://bliptext.com/articles/blood), [pre-ejaculate](https://bliptext.com/articles/pre-ejaculate), [semen](https://bliptext.com/articles/semen), and [vaginal fluids](https://bliptext.com/articles/vaginal-lubrication).\nNon-sexual transmission can occur from an infected mother to her infant during [pregnancy](https://bliptext.com/articles/pregnancy), during [childbirth](https://bliptext.com/articles/childbirth) by exposure to her blood or vaginal fluid, and through [breast milk](https://bliptext.com/articles/breast-milk).\nWithin these bodily fluids, HIV is present as both free [virus](https://bliptext.com/articles/virus) particles and [virus](https://bliptext.com/articles/virus) within infected [immune cells](https://bliptext.com/articles/white-blood-cell).\nResearch has shown (for both same-sex and opposite-sex couples) that HIV is not contagious during sexual intercourse without a condom if the HIV-positive partner has a consistently undetectable [viral load](https://bliptext.com/articles/viral-load-monitoring-for-hiv).\nHIV infects vital cells in the human immune system, such as [helper T cells](https://bliptext.com/articles/t-helper-cell) (specifically [CD4](https://bliptext.com/articles/cd4) + T cells), [macrophages](https://bliptext.com/articles/macrophage), and [dendritic cells](https://bliptext.com/articles/dendritic-cell).\nHIV infection leads to low levels of CD4 + T cells through a number of mechanisms, including [pyroptosis](https://bliptext.com/articles/pyroptosis) of abortively infected T cells, [apoptosis](https://bliptext.com/articles/apoptosis) of uninfected bystander cells, direct viral killing of infected cells, and killing of infected CD4 + T cells by [CD8 + cytotoxic lymphocytes](https://bliptext.com/articles/cd8-cytotoxic-lymphocyte) that recognize infected cells.\nWhen CD4 + T cell numbers decline below a critical level, [cell-mediated immunity](https://bliptext.com/articles/cell-mediated-immunity) is lost, and the body becomes progressively more susceptible to opportunistic infections, leading to the development of AIDS.\n\n# Virology\n\n## Classification\nHIV is a member of the [genus](https://bliptext.com/articles/genus) [Lentivirus](https://bliptext.com/articles/lentivirus), part of the family [Retroviridae](https://bliptext.com/articles/retroviridae).\nLentiviruses have many [morphologies](https://bliptext.com/articles/morphology-biology) and [biological](https://bliptext.com/articles/biology) properties in common.\nMany species are infected by lentiviruses, which are characteristically responsible for long-duration illnesses with a long [incubation period](https://bliptext.com/articles/incubation-period).\nLentiviruses are transmitted as [single-stranded](https://bliptext.com/articles/single-stranded), positive-[sense](https://bliptext.com/articles/sense-molecular-biology), [enveloped](https://bliptext.com/articles/viral-envelope) [RNA viruses](https://bliptext.com/articles/rna-virus).\nUpon entry into the target cell, the viral [RNA](https://bliptext.com/articles/rna) [genome](https://bliptext.com/articles/genome) is converted (reverse transcribed) into double-stranded [DNA](https://bliptext.com/articles/dna) by a virally encoded enzyme, [reverse transcriptase](https://bliptext.com/articles/reverse-transcriptase), that is transported along with the viral [genome](https://bliptext.com/articles/genome) in the virus particle.\nThe resulting viral DNA is then imported into the [cell nucleus](https://bliptext.com/articles/cell-nucleus) and integrated into the cellular DNA by a virally encoded enzyme, [integrase](https://bliptext.com/articles/integrase), and host [co-factors](https://bliptext.com/articles/cofactor-biochemistry).\nOnce integrated, the virus may become [latent](https://bliptext.com/articles/virus-latency), allowing the virus and its host cell to avoid detection by the immune system, for an indeterminate amount of time.\nThe virus can remain dormant in the human body for up to ten years after primary infection; during this period the virus does not cause symptoms.\nAlternatively, the integrated viral DNA may be [transcribed](https://bliptext.com/articles/transcription-genetics), producing new RNA genomes and viral proteins, using host cell resources, that are packaged and released from the cell as new virus particles that will begin the replication cycle anew.\nTwo types of HIV have been characterized: HIV-1 and HIV-2.\nHIV-1 is the virus that was initially discovered and termed both lymphadenopathy associated virus (LAV) and human T-lymphotropic virus 3 (HTLV-III).\nHIV-1 is more [virulent](https://bliptext.com/articles/virulence) and more [infective](https://bliptext.com/articles/infectivity) than HIV-2, and is the cause of the majority of HIV infections globally.\nThe lower infectivity of HIV-2, compared to HIV-1, implies that fewer of those exposed to HIV-2 will be infected per exposure.\nDue to its relatively poor capacity for transmission, HIV-2 is largely confined to [West Africa](https://bliptext.com/articles/west-africa).\n\n## Structure and genome\nHIV is similar in structure to other retroviruses.\nIt is roughly spherical with a diameter of about 120 [nm](https://bliptext.com/articles/nanometre), around 100,000 times smaller in volume than a [red blood cell](https://bliptext.com/articles/red-blood-cell).\nIt is composed of two copies of positive-[sense](https://bliptext.com/articles/sense-molecular-biology) [single-stranded](https://bliptext.com/articles/single-stranded) [RNA](https://bliptext.com/articles/rna) that codes for the virus' nine [genes](https://bliptext.com/articles/gene) enclosed by a conical [capsid](https://bliptext.com/articles/capsid) composed of 2,000 copies of the viral protein [p24](https://bliptext.com/articles/p24-capsid-protein).\nThe single-stranded RNA is tightly bound to nucleocapsid proteins, p7, and enzymes needed for the development of the virion such as [reverse transcriptase](https://bliptext.com/articles/reverse-transcriptase), [proteases](https://bliptext.com/articles/protease), [ribonuclease](https://bliptext.com/articles/ribonuclease) and [integrase](https://bliptext.com/articles/integrase).\nA matrix composed of the viral protein p17 surrounds the capsid ensuring the integrity of the virion particle.\nThis is, in turn, surrounded by the [viral envelope](https://bliptext.com/articles/viral-envelope), that is composed of the [lipid bilayer](https://bliptext.com/articles/lipid-bilayer) taken from the membrane of a human host cell when the newly formed virus particle buds from the cell.\nThe viral envelope contains proteins from the host cell and relatively few copies of the HIV envelope protein, which consists of a cap made of three molecules known as [glycoprotein (gp) 120](https://bliptext.com/articles/gp120), and a stem consisting of three [gp41](https://bliptext.com/articles/gp41) molecules that anchor the structure into the viral envelope.\nThe envelope protein, encoded by the HIV env gene, allows the virus to attach to target cells and fuse the viral envelope with the target [cell's membrane](https://bliptext.com/articles/cell-membrane) releasing the viral contents into the cell and initiating the infectious cycle.\nAs the sole viral protein on the surface of the virus, the envelope protein is a major target for [HIV vaccine](https://bliptext.com/articles/hiv-vaccine) efforts.\nOver half of the mass of the trimeric envelope spike is N-linked [glycans](https://bliptext.com/articles/glycan).\nThe density is high as the glycans shield the underlying viral protein from neutralisation by antibodies.\nThis is one of the most densely glycosylated molecules known and the density is sufficiently high to prevent the normal maturation process of glycans during biogenesis in the endoplasmic and Golgi apparatus.\nThe majority of the glycans are therefore stalled as immature 'high-mannose' glycans not normally present on human glycoproteins that are secreted or present on a cell surface.\nThe unusual processing and high density means that almost all broadly neutralising antibodies that have so far been identified (from a subset of patients that have been infected for many months to years) bind to, or are adapted to cope with, these envelope glycans.\nThe molecular structure of the viral spike has now been determined by [X-ray crystallography](https://bliptext.com/articles/x-ray-crystallography) and [cryogenic electron microscopy](https://bliptext.com/articles/cryogenic-electron-microscopy).\nThese advances in structural biology were made possible due to the development of stable [recombinant](https://bliptext.com/articles/recombinant-organism) forms of the viral spike by the introduction of an intersubunit [disulphide bond](https://bliptext.com/articles/disulphide-bond) and an [isoleucine](https://bliptext.com/articles/isoleucine) to [proline](https://bliptext.com/articles/proline) [mutation](https://bliptext.com/articles/mutation) ([radical replacement](https://bliptext.com/articles/radical-replacement) of an amino acid) in gp41.\nThe so-called SOSIP [trimers](https://bliptext.com/articles/trimer-chemistry) not only reproduce the antigenic properties of the native viral spike, but also display the same degree of immature glycans as presented on the native virus.\nRecombinant trimeric viral spikes are promising vaccine candidates as they display less non-neutralising [epitopes](https://bliptext.com/articles/epitope) than recombinant monomeric gp120, which act to suppress the immune response to target [epitopes](https://bliptext.com/articles/epitope).\nThe RNA genome consists of at least seven structural landmarks ([LTR](https://bliptext.com/articles/long-terminal-repeat), [TAR](https://bliptext.com/articles/trans-activation-response-element-tar), [RRE](https://bliptext.com/articles/hiv-rev-response-element), PE, SLIP, CRS, and INS), and nine genes (gag, pol, and env, tat, rev, nef, vif, vpr, vpu, and sometimes a tenth tev, which is a fusion of tat, env and rev), encoding 19 proteins.\nThree of these genes, gag, pol, and env, contain information needed to make the structural proteins for new virus particles.\nFor example, env codes for a protein called gp160 that is cut in two by a cellular protease to form gp120 and gp41.\nThe six remaining genes, tat, rev, nef, vif, vpr, and vpu (or vpx in the case of HIV-2), are regulatory genes for proteins that control the ability of HIV to infect cells, produce new copies of virus (replicate), or cause disease.\nThe two [tat](https://bliptext.com/articles/tat-hiv) proteins (p16 and p14) are [transcriptional transactivators](https://bliptext.com/articles/activator-genetics) for the LTR [promoter](https://bliptext.com/articles/promoter-genetics) acting by binding the TAR RNA element.\nThe TAR may also be processed into [microRNAs](https://bliptext.com/articles/microrna) that regulate the [apoptosis](https://bliptext.com/articles/apoptosis) genes [ERCC1](https://bliptext.com/articles/ercc1) and [IER3](https://bliptext.com/articles/ier3).\nThe rev protein (p19) is involved in shuttling RNAs from the nucleus and the cytoplasm by binding to the [RRE](https://bliptext.com/articles/hiv-rev-response-element) RNA element.\nThe vif protein (p23) prevents the action of [APOBEC3G](https://bliptext.com/articles/apobec3g) (a cellular protein that [deaminates](https://bliptext.com/articles/deamination) [cytidine](https://bliptext.com/articles/cytidine) to [uridine](https://bliptext.com/articles/uridine) in the single-stranded viral DNA and/or interferes with reverse transcription ).\nThe [vpr](https://bliptext.com/articles/vpr) protein (p14) arrests [cell division](https://bliptext.com/articles/cell-division) at [G2/M](https://bliptext.com/articles/g2-m-checkpoint).\nThe nef protein (p27) down-regulates [CD4](https://bliptext.com/articles/cd4) (the major viral receptor), as well as the [MHC class I](https://bliptext.com/articles/mhc-class-i) and [class II](https://bliptext.com/articles/mhc-class-ii) molecules.\nNef also interacts with [SH3 domains](https://bliptext.com/articles/sh3-domain).\nThe vpu protein (p16) influences the release of new virus particles from infected cells.\nThe ends of each strand of HIV RNA contain an RNA sequence called a [long terminal repeat](https://bliptext.com/articles/long-terminal-repeat) (LTR).\nRegions in the LTR act as switches to control production of new viruses and can be triggered by proteins from either HIV or the host cell.\nThe [Psi element](https://bliptext.com/articles/retroviral-psi-packaging-element) is involved in viral genome packaging and recognized by gag and rev proteins.\nThe SLIP element is involved in the [frameshift](https://bliptext.com/articles/translational-frameshift) in the gag-pol [reading frame](https://bliptext.com/articles/reading-frame) required to make functional pol.\n# [Diagram of the HIV virion | upload.wikimedia.org/wikipedia/commons/5/5e/HI-virion-structure///en.svg]\n# [A diagram of the HIV spike protein (green), with the fusion peptide epitope highlighted in red, and a broadly neutralizing antibody (yellow) binding to the fusion peptide | upload.wikimedia.org/wikipedia/commons/8/88/Protein///Structure///Diagram///of///Fusion///Peptide///Epitope///on///HIV///Spike///%2841863579304%29.jpg]\n# [Structure of the RNA genome of HIV-1 | upload.wikimedia.org/wikipedia/commons/c/c6/HIV-genome.png]\n\n## Tropism\nThe term [viral tropism](https://bliptext.com/articles/viral-tropism) refers to the cell types a virus infects.\nHIV can infect a variety of immune cells such as [CD4 + T cells](https://bliptext.com/articles/helper-t-cell), [macrophages](https://bliptext.com/articles/macrophage), and [microglial cells](https://bliptext.com/articles/microglial-cell).\nHIV-1 entry to macrophages and CD4 + T cells is mediated through interaction of the virion envelope glycoproteins (gp120) with the CD4 molecule on the target cells' membrane and also with [chemokine](https://bliptext.com/articles/chemokine) [co-receptors](https://bliptext.com/articles/co-receptor).\nMacrophage-tropic (M-tropic) strains of HIV-1, or non-[syncytia](https://bliptext.com/articles/syncytia)-inducing strains (NSI; now called R5 viruses ) use the β-chemokine receptor, [CCR5](https://bliptext.com/articles/ccr5), for entry and are thus able to replicate in both macrophages and CD4 + T cells.\nThis CCR5 co-receptor is used by almost all primary HIV-1 isolates regardless of viral genetic subtype.\nIndeed, macrophages play a key role in several critical aspects of HIV infection.\nThey appear to be the first cells infected by HIV and perhaps the source of HIV production when CD4 + cells become depleted in the patient.\nMacrophages and microglial cells are the cells infected by HIV in the [central nervous system](https://bliptext.com/articles/central-nervous-system).\nIn the [tonsils](https://bliptext.com/articles/tonsil) and [adenoids](https://bliptext.com/articles/adenoids) of HIV-infected patients, macrophages fuse into multinucleated [giant cells](https://bliptext.com/articles/giant-cell) that produce huge amounts of virus.\nT-tropic strains of HIV-1, or [syncytia](https://bliptext.com/articles/syncytia)-inducing strains (SI; now called X4 viruses ) replicate in primary CD4 + T cells as well as in macrophages and use the α-chemokine receptor, [CXCR4](https://bliptext.com/articles/cxcr4), for entry.\nDual-tropic HIV-1 strains are thought to be transitional strains of HIV-1 and thus are able to use both CCR5 and CXCR4 as co-receptors for viral entry.\nThe α-chemokine [SDF-1](https://bliptext.com/articles/sdf-1-biology), a [ligand](https://bliptext.com/articles/ligand-biochemistry) for CXCR4, suppresses replication of T-tropic HIV-1 isolates.\nIt does this by [down-regulating](https://bliptext.com/articles/downregulation-and-upregulation) the expression of CXCR4 on the surface of HIV target cells.\nM-tropic HIV-1 isolates that use only the CCR5 receptor are termed R5; those that use only CXCR4 are termed X4, and those that use both, X4R5.\nHowever, the use of co-receptors alone does not explain viral tropism, as not all R5 viruses are able to use CCR5 on macrophages for a productive infection and HIV can also infect a subtype of [myeloid dendritic cells](https://bliptext.com/articles/myeloid-dendritic-cells), which probably constitute a [reservoir](https://bliptext.com/articles/natural-reservoir) that maintains infection when CD4 + T cell numbers have declined to extremely low levels.\nSome people are resistant to certain strains of HIV.\nFor example, people with the [CCR5-Δ32](https://bliptext.com/articles/ccr5-32) mutation are resistant to infection by the R5 virus, as the mutation leaves HIV unable to bind to this co-receptor, reducing its ability to infect target cells.\n[Sexual intercourse](https://bliptext.com/articles/sexual-intercourse) is the major mode of HIV transmission.\nBoth X4 and R5 HIV are present in the [seminal fluid](https://bliptext.com/articles/seminal-fluid), which enables the virus to be transmitted from a male to his [sexual partner](https://bliptext.com/articles/sexual-partner).\nThe virions can then infect numerous cellular targets and disseminate into the whole organism.\nHowever, a selection process leads to a predominant transmission of the R5 virus through this pathway.\nIn patients infected with subtype B HIV-1, there is often a co-receptor switch in late-stage disease and T-tropic variants that can infect a variety of T cells through CXCR4.\nThese variants then replicate more aggressively with heightened virulence that causes rapid T cell depletion, immune system collapse, and opportunistic infections that mark the advent of AIDS.\nHIV-positive patients acquire an enormously broad spectrum of opportunistic infections, which was particularly problematic prior to the onset of [HAART](https://bliptext.com/articles/management-of-hiv-aids) therapies; however, the same infections are reported among HIV-infected patients examined post-mortem following the onset of antiretroviral therapies.\nThus, during the course of infection, viral adaptation to the use of CXCR4 instead of CCR5 may be a key step in the progression to AIDS.\nA number of studies with subtype B-infected individuals have determined that between 40 and 50 percent of AIDS patients can harbour viruses of the SI and, it is presumed, the X4 phenotypes.\nHIV-2 is much less pathogenic than HIV-1 and is restricted in its worldwide distribution to [West Africa](https://bliptext.com/articles/west-africa).\nThe adoption of \"accessory genes\" by HIV-2 and its more [promiscuous](https://bliptext.com/articles/enzyme-promiscuity) pattern of co-receptor usage (including CD4-independence) may assist the virus in its adaptation to avoid innate restriction factors present in host cells.\nAdaptation to use normal cellular machinery to enable transmission and productive infection has also aided the establishment of HIV-2 replication in humans.\nA survival strategy for any infectious agent is not to kill its host, but ultimately become a [commensal](https://bliptext.com/articles/commensal) organism.\nHaving achieved a low pathogenicity, over time, variants that are more successful at transmission will be selected.\n# [Diagram of the immature and mature forms of HIV | upload.wikimedia.org/wikipedia/commons/0/00/HIV///Mature///and///Immature.PNG]\n\n## Replication cycle\n# [The HIV replication cycle | upload.wikimedia.org/wikipedia/commons/5/57/HIV-replication-cycle-en.svg]\n\n### Entry to the cell\nThe HIV virion enters [macrophages](https://bliptext.com/articles/macrophage) and CD4 + [T cells](https://bliptext.com/articles/t-cells) by the [adsorption](https://bliptext.com/articles/adsorption) of [glycoproteins](https://bliptext.com/articles/glycoprotein) on its surface to receptors on the target cell followed by fusion of the [viral envelope](https://bliptext.com/articles/viral-envelope) with the target cell membrane and the release of the HIV capsid into the cell.\nEntry to the cell begins through interaction of the trimeric envelope complex ([gp160](https://bliptext.com/articles/gp160) spike) on the HIV viral envelope and both [CD4](https://bliptext.com/articles/cd4) and a chemokine co-receptor (generally either [CCR5](https://bliptext.com/articles/ccr5) or [CXCR4](https://bliptext.com/articles/cxcr4), but others are known to interact) on the target cell surface.\nGp120 binds to [integrin](https://bliptext.com/articles/integrin) α4β7 activating [LFA-1](https://bliptext.com/articles/lfa-1), the central [integrin](https://bliptext.com/articles/integrin) involved in the establishment of [virological synapses](https://bliptext.com/articles/virological-synapse), which facilitate efficient cell-to-cell spreading of HIV-1.\nThe gp160 spike contains binding domains for both CD4 and chemokine receptors.\nThe first step in fusion involves the high-affinity attachment of the CD4 binding domains of [gp120](https://bliptext.com/articles/gp120) to CD4.\nOnce gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine receptor binding domains of gp120 and allowing them to interact with the target chemokine receptor.\nThis allows for a more stable two-pronged attachment, which allows the [N-terminal](https://bliptext.com/articles/n-terminus) fusion peptide gp41 to penetrate the cell membrane.\n[Repeat sequences](https://bliptext.com/articles/repeated-sequence-dna) in gp41, HR1, and HR2 then interact, causing the collapse of the extracellular portion of gp41 into a hairpin shape.\nThis loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.\nAfter HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase, ribonuclease, and protease, are injected into the cell.\nDuring the [microtubule](https://bliptext.com/articles/microtubule)-based transport to the nucleus, the viral single-strand RNA genome is transcribed into double-strand DNA, which is then integrated into a host chromosome.\nHIV can infect [dendritic cells](https://bliptext.com/articles/dendritic-cell) (DCs) by this CD4-CCR5 route, but another route using [mannose-specific C-type lectin receptors](https://bliptext.com/articles/mannose-receptor) such as [DC-SIGN](https://bliptext.com/articles/dc-sign) can also be used.\nDCs are one of the first cells encountered by the virus during sexual transmission.\nThey are currently thought to play an important role by transmitting HIV to T cells when the virus is captured in the [mucosa](https://bliptext.com/articles/mucosa) by DCs.\nThe presence of [FEZ-1](https://bliptext.com/articles/fez-1), which occurs naturally in [neurons](https://bliptext.com/articles/neuron), is believed to prevent the infection of cells by HIV.\nHIV-1 entry, as well as entry of many other retroviruses, has long been believed to occur exclusively at the plasma membrane.\nMore recently, however, productive infection by [pH](https://bliptext.com/articles/ph)-independent, [clathrin-mediated endocytosis](https://bliptext.com/articles/clathrin-mediated-endocytosis) of HIV-1 has also been reported and was recently suggested to constitute the only route of productive entry.\n# [Mechanism of viral entry: 1. Initial interaction between gp120 and CD4. 2. Conformational change in gp120 allows for secondary interaction with CXCR4. 3. The distal tips of gp41 are inserted into the cellular membrane. 4. gp41 undergoes significant conformational change; folding in half and forming coiled-coils. This process pulls the viral and cellular membranes together, fusing them. | upload.wikimedia.org/wikipedia/commons/6/61/HIV///Membrane///fusion///panel.svg]\n# [Clathrin-mediated endocytosis | upload.wikimedia.org/wikipedia/commons/4/47/Itrafig2.jpg]\n\n### Replication and transcription\nShortly after the viral capsid enters the cell, an [enzyme](https://bliptext.com/articles/enzyme) called [reverse transcriptase](https://bliptext.com/articles/reverse-transcriptase) liberates the positive-sense single-stranded [RNA](https://bliptext.com/articles/rna) genome from the attached viral proteins and copies it into a [complementary DNA](https://bliptext.com/articles/cdna) (cDNA) molecule.\nThe process of reverse transcription is extremely error-prone, and the resulting mutations may cause [drug resistance](https://bliptext.com/articles/resistance-to-antiviral-drugs) or allow the virus to evade the body's immune system.\nThe reverse transcriptase also has ribonuclease activity that degrades the viral RNA during the synthesis of cDNA, as well as DNA-dependent DNA polymerase activity that creates a [sense](https://bliptext.com/articles/sense-molecular-biology) DNA from the anti[sense](https://bliptext.com/articles/sense-molecular-biology) cDNA.\nTogether, the cDNA and its complement form a double-stranded viral DNA that is then transported into the [cell nucleus](https://bliptext.com/articles/cell-nucleus).\nThe integration of the viral DNA into the host cell's [genome](https://bliptext.com/articles/genome) is carried out by another viral enzyme called [integrase](https://bliptext.com/articles/integrase).\nThe integrated viral DNA may then lie dormant, in the latent stage of HIV infection.\nTo actively produce the virus, certain cellular [transcription factors](https://bliptext.com/articles/transcription-factor) need to be present, the most important of which is NF-κB (nuclear factor kappa B), which is upregulated when T cells become activated.\nThis means that those cells most likely to be targeted, entered and subsequently killed by HIV are those actively fighting infection.\nDuring viral replication, the integrated DNA [provirus](https://bliptext.com/articles/provirus) is [transcribed](https://bliptext.com/articles/transcription-genetics) into RNA.\nThe full-length genomic RNAs (gRNA) can be packaged into new viral particles in a [pseudodiploid](https://bliptext.com/articles/pseudodiploid) form.\nThe selectivity in the packaging is explained by the structural properties of the dimeric conformer of the gRNA.\nThe gRNA dimer is characterized by a tandem three-way junction within the gRNA monomer, in which the SD and AUG [hairpins](https://bliptext.com/articles/stem-loop), responsible for splicing and translation respectively, are sequestered and the DIS (dimerization initiation signal) hairpin is exposed.\nThe formation of the gRNA dimer is mediated by a 'kissing' interaction between the DIS hairpin loops of the gRNA monomers.\nAt the same time, certain guanosine residues in the gRNA are made available for binding of the nucleocapsid (NC) protein leading to the subsequent virion assembly.\nThe labile gRNA dimer has been also reported to achieve a more stable conformation following the NC binding, in which both the DIS and the U5:AUG regions of the gRNA participate in extensive base pairing.\nRNA can also be [processed](https://bliptext.com/articles/post-transcriptional-modification) to produce mature [messenger RNAs](https://bliptext.com/articles/messenger-rna) (mRNAs).\nIn most cases, this processing involves [RNA splicing](https://bliptext.com/articles/rna-splicing) to produce mRNAs that are shorter than the full-length genome.\nWhich part of the RNA is removed during RNA splicing determines which of the HIV protein-coding sequences is translated.\nMature HIV mRNAs are exported from the nucleus into the [cytoplasm](https://bliptext.com/articles/cytoplasm), where they are [translated](https://bliptext.com/articles/translation-genetics) to produce HIV proteins, including [Rev](https://bliptext.com/articles/rev-hiv).\nAs the newly produced Rev protein is produced it moves to the nucleus, where it binds to full-length, unspliced copies of virus RNAs and allows them to leave the nucleus.\nSome of these full-length RNAs function as mRNAs that are translated to produce the structural proteins Gag and Env.\nGag proteins bind to copies of the virus RNA genome to package them into new virus particles.\nHIV-1 and HIV-2 appear to package their RNA differently.\nHIV-1 will bind to any appropriate RNA.\nHIV-2 will preferentially bind to the mRNA that was used to create the Gag protein itself.\n# [Reverse transcription of the HIV genome into double-stranded DNA | upload.wikimedia.org/wikipedia/commons/a/aa/Reverse///Transcription.png]\n\n### Recombination\nTwo RNA genomes are encapsidated in each HIV-1 particle (see [Structure and genome of HIV](https://bliptext.com/articles/structure-and-genome-of-hiv)).\nUpon infection and replication catalyzed by reverse transcriptase, recombination between the two genomes can occur.\nRecombination occurs as the single-strand, positive-sense RNA genomes are reverse transcribed to form DNA.\nDuring reverse transcription, the nascent DNA can switch multiple times between the two copies of the viral RNA.\nThis form of recombination is known as copy-choice.\nRecombination events may occur throughout the genome.\nAnywhere from two to 20 recombination events per genome may occur at each replication cycle, and these events can rapidly shuffle the genetic information that is transmitted from parental to progeny genomes.\nViral recombination produces genetic variation that likely contributes to the [evolution](https://bliptext.com/articles/evolution) of resistance to [anti-retroviral therapy](https://bliptext.com/articles/management-of-hiv-aids).\nRecombination may also contribute, in principle, to overcoming the immune defenses of the host.\nYet, for the adaptive advantages of genetic variation to be realized, the two viral genomes packaged in individual infecting virus particles need to have arisen from separate progenitor parental viruses of differing genetic constitution.\nIt is unknown how often such mixed packaging occurs under natural conditions.\nBonhoeffer et al. suggested that template switching by reverse transcriptase acts as a repair process to deal with breaks in the single-stranded RNA genome.\nIn addition, Hu and Temin suggested that recombination is an adaptation for repair of damage in the RNA genomes.\nStrand switching (copy-choice recombination) by reverse transcriptase could generate an undamaged copy of genomic DNA from two damaged single-stranded RNA genome copies.\nThis view of the adaptive benefit of recombination in HIV could explain why each HIV particle contains two complete genomes, rather than one.\nFurthermore, the view that recombination is a repair process implies that the benefit of repair can occur at each replication cycle, and that this benefit can be realized whether or not the two genomes differ genetically.\nOn the view that recombination in HIV is a repair process, the generation of recombinational variation would be a consequence, but not the cause of, the evolution of template switching.\nHIV-1 infection causes [chronic inflammation](https://bliptext.com/articles/chronic-inflammation) and production of [reactive oxygen species](https://bliptext.com/articles/reactive-oxygen-species).\nThus, the HIV genome may be vulnerable to [oxidative damage](https://bliptext.com/articles/oxidative-damage), including breaks in the single-stranded RNA.\nFor HIV, as well as for viruses in general, successful infection depends on overcoming host defense strategies that often include production of genome-damaging reactive oxygen species.\nThus, Michod et al. suggested that recombination by viruses is an adaptation for repair of genome damage, and that recombinational variation is a byproduct that may provide a separate benefit.\n\n### Assembly and release\nThe final step of the viral cycle, assembly of new HIV-1 virions, begins at the [plasma membrane](https://bliptext.com/articles/plasma-membrane) of the host cell.\nThe Env polyprotein (gp160) goes through the [endoplasmic reticulum](https://bliptext.com/articles/endoplasmic-reticulum) and is transported to the [Golgi apparatus](https://bliptext.com/articles/golgi-apparatus) where it is [cleaved](https://bliptext.com/articles/bond-cleavage) by [furin](https://bliptext.com/articles/furin) resulting in the two HIV envelope glycoproteins, [gp41](https://bliptext.com/articles/gp41) and [gp120](https://bliptext.com/articles/gp120).\nThese are transported to the plasma membrane of the host cell where gp41 anchors gp120 to the membrane of the infected cell.\nThe Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the HIV genomic RNA as the forming virion begins to bud from the host cell.\nThe budded virion is still immature as the [gag](https://bliptext.com/articles/group-specific-antigen) polyproteins still need to be cleaved into the actual matrix, capsid and nucleocapsid proteins.\nThis cleavage is mediated by the packaged viral protease and can be inhibited by antiretroviral drugs of the [protease inhibitor](https://bliptext.com/articles/protease-inhibitor-pharmacology) class.\nThe various structural components then assemble to produce a mature HIV virion.\nOnly mature virions are then able to infect another cell.\n# [HIV assembling on the surface of an infected macrophage. The HIV virions have been marked with a green fluorescent tag and then viewed under a fluorescent microscope. | upload.wikimedia.org/wikipedia/commons/a/a7/HIV///on///macrophage.png]\n\n## Spread within the body\nThe classical process of infection of a cell by a virion can be called \"cell-free spread\" to distinguish it from a more recently recognized process called \"cell-to-cell spread\".\nIn cell-free spread (see figure), virus particles bud from an infected T cell, enter the blood or [extracellular fluid](https://bliptext.com/articles/extracellular-fluid) and then infect another T cell following a chance encounter.\nHIV can also disseminate by direct transmission from one cell to another by a process of cell-to-cell spread, for which two pathways have been described.\nFirstly, an infected T cell can transmit virus directly to a target T cell via a [virological synapse](https://bliptext.com/articles/viral-synapse).\nSecondly, an [antigen-presenting cell](https://bliptext.com/articles/antigen-presenting-cell) (APC), such as a macrophage or dendritic cell, can transmit HIV to T cells by a process that either involves productive infection (in the case of macrophages) or capture and transfer of virions in trans (in the case of dendritic cells).\nWhichever pathway is used, infection by cell-to-cell transfer is reported to be much more efficient than cell-free virus spread.\nA number of factors contribute to this increased efficiency, including polarised virus budding towards the site of cell-to-cell contact, close apposition of cells, which minimizes fluid-phase [diffusion](https://bliptext.com/articles/diffusion) of virions, and clustering of HIV entry receptors on the target cell towards the contact zone.\nCell-to-cell spread is thought to be particularly important in [lymphoid tissues](https://bliptext.com/articles/lymphoid-tissue), where CD4+ T cells are densely packed and likely to interact frequently.\n[Intravital imaging](https://bliptext.com/articles/intravital-microscopy) studies have supported the concept of the HIV virological synapse in vivo.\nThe many dissemination mechanisms available to HIV contribute to the virus' ongoing replication in spite of anti-retroviral therapies.\n\n## Genetic variability\nHIV differs from many viruses in that it has very high [genetic variability](https://bliptext.com/articles/genetic-variability).\nThis diversity is a result of its fast [replication cycle](https://bliptext.com/articles/), with the generation of about 1010 virions every day, coupled with a high [mutation rate](https://bliptext.com/articles/mutation-rate) of approximately 3 x 10−5 per [nucleotide base](https://bliptext.com/articles/nucleobase) per cycle of replication and [recombinogenic](https://bliptext.com/articles/genetic-recombination) properties of reverse transcriptase.\nThis complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day.\nThis variability is compounded when a single cell is simultaneously infected by two or more different strains of HIV.\nWhen [simultaneous infection](https://bliptext.com/articles/coinfection) occurs, the genome of progeny virions may be composed of RNA strands from two different strains.\nThis hybrid virion then infects a new cell where it undergoes replication.\nAs this happens, the reverse transcriptase, by jumping back and forth between the two different RNA templates, will generate a newly synthesized retroviral [DNA sequence](https://bliptext.com/articles/dna-sequence) that is a recombinant between the two parental genomes.\nThis recombination is most obvious when it occurs between subtypes.\nThe closely related [simian immunodeficiency virus](https://bliptext.com/articles/simian-immunodeficiency-virus) (SIV) has evolved into many strains, classified by the natural host species.\nSIV strains of the [African green monkey](https://bliptext.com/articles/chlorocebus) (SIVagm) and [sooty mangabey](https://bliptext.com/articles/sooty-mangabey) (SIVsmm) are thought to have a long evolutionary history with their hosts.\nThese hosts have adapted to the presence of the virus, which is present at high levels in the host's blood, but evokes only a mild immune response, does not cause the development of simian AIDS, and does not undergo the extensive mutation and recombination typical of HIV infection in humans.\nIn contrast, when these strains infect species that have not adapted to SIV (\"heterologous\" or similar hosts such as [rhesus](https://bliptext.com/articles/rhesus-macaque) or [cynomologus macaques](https://bliptext.com/articles/crab-eating-macaque)), the animals develop AIDS and the virus generates [genetic diversity](https://bliptext.com/articles/genetic-diversity) similar to what is seen in human HIV infection.\n[Chimpanzee](https://bliptext.com/articles/common-chimpanzee) SIV (SIVcpz), the closest genetic relative of HIV-1, is associated with increased mortality and AIDS-like symptoms in its natural host.\nSIVcpz appears to have been transmitted relatively recently to chimpanzee and human populations, so their hosts have not yet adapted to the virus.\nThis virus has also lost a function of the [nef](https://bliptext.com/articles/nef-protein) gene that is present in most SIVs.\nFor non-pathogenic SIV variants, nef suppresses T cell activation through the [CD3](https://bliptext.com/articles/cd3-immunology) marker.\nNef function in non-pathogenic forms of SIV is to [downregulate](https://bliptext.com/articles/downregulation-and-upregulation) expression of [inflammatory cytokines](https://bliptext.com/articles/proinflammatory-cytokine), [MHC-1](https://bliptext.com/articles/mhc-class-i), and signals that affect T cell trafficking.\nIn HIV-1 and SIVcpz, nef does not inhibit T-cell activation and it has lost this function.\nWithout this function, T cell depletion is more likely, leading to immunodeficiency.\nThree groups of HIV-1 have been identified on the basis of differences in the envelope (env) region: M, N, and O. Group M is the most prevalent and is subdivided into eight subtypes (or [clades](https://bliptext.com/articles/clade)), based on the whole genome, which are geographically distinct.\nThe most prevalent are subtypes B (found mainly in North America and Europe), A and D (found mainly in Africa), and C (found mainly in Africa and Asia); these subtypes form branches in the [phylogenetic tree](https://bliptext.com/articles/phylogenetic-tree) representing the lineage of the M group of HIV-1.\n[Co-infection](https://bliptext.com/articles/coinfection) with distinct subtypes gives rise to circulating recombinant forms (CRFs).\nIn 2000, the last year in which an analysis of global subtype prevalence was made, 47.2% of infections worldwide were of subtype C, 26.7% were of subtype A/CRF02_AG, 12.3% were of subtype B, 5.3% were of subtype D, 3.2% were of CRF_AE, and the remaining 5.3% were composed of other subtypes and CRFs.\nMost HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes.\nThe existence of a fourth group, \"P\", has been hypothesised based on a virus isolated in 2009.\nThe strain is apparently derived from [gorilla](https://bliptext.com/articles/gorilla-gorilla) SIV (SIVgor), first isolated from western lowland [gorilla](https://bliptext.com/articles/gorilla-gorilla)s in 2006.\nHIV-2's closest relative is SIVsm, a strain of SIV found in sooty mangabees.\nSince HIV-1 is derived from SIVcpz, and HIV-2 from SIVsm, the genetic sequence of HIV-2 is only partially homologous to HIV-1 and more closely resembles that of SIVsm.\n# [The phylogenetic tree of the SIV and HIV | upload.wikimedia.org/wikipedia/commons/f/fb/HIV-SIV-phylogenetic-tree///straight.svg]\n\n# Diagnosis\nMany HIV-positive people are unaware that they are infected with the virus.\nFor example, in 2001 less than 1% of the sexually active urban population in Africa had been tested, and this proportion is even lower in rural populations.\nFurthermore, in 2001 only 0.5% of [pregnant women](https://bliptext.com/articles/pregnancy) attending urban health facilities were counselled, tested or received their test results.\nAgain, this proportion is even lower in rural health facilities.\nSince donors may therefore be unaware of their infection, [donor blood](https://bliptext.com/articles/blood-donation) and blood products used in medicine and [medical research](https://bliptext.com/articles/medical-research) are routinely screened for HIV.\nHIV-1 testing is initially done using an [enzyme-linked immunosorbent assay](https://bliptext.com/articles/enzyme-linked-immunosorbent-assay) (ELISA) to detect antibodies to HIV-1.\nSpecimens with a non-reactive result from the initial ELISA are considered HIV-negative, unless new exposure to an infected partner or partner of unknown HIV status has occurred.\nSpecimens with a reactive ELISA result are retested in duplicate.\nIf the result of either duplicate test is reactive, the specimen is reported as repeatedly reactive and undergoes confirmatory testing with a more specific supplemental test (e.g., a [polymerase chain reaction](https://bliptext.com/articles/polymerase-chain-reaction) (PCR), [western blot](https://bliptext.com/articles/western-blot) or, less commonly, an [immunofluorescence assay](https://bliptext.com/articles/immunofluorescence-assay) (IFA)).\nOnly specimens that are repeatedly reactive by ELISA and positive by IFA or PCR or reactive by western blot are considered HIV-positive and indicative of HIV infection.\nSpecimens that are repeatedly ELISA-reactive occasionally provide an indeterminate western blot result, which may be either an incomplete antibody response to HIV in an infected person or nonspecific reactions in an uninfected person.\nAlthough IFA can be used to confirm infection in these ambiguous cases, this assay is not widely used.\nIn general, a second specimen should be collected more than a month later and retested for persons with indeterminate western blot results.\nAlthough much less commonly available, [nucleic acid testing](https://bliptext.com/articles/nucleic-acid-test) (e.g., viral RNA or proviral DNA amplification method) can also help diagnosis in certain situations.\nIn addition, a few tested specimens might provide inconclusive results because of a low quantity specimen.\nIn these situations, a second specimen is collected and tested for HIV infection.\nModern HIV testing is extremely accurate, when the [window period](https://bliptext.com/articles/window-period) is taken into consideration.\nA single screening test is correct more than 99% of the time.\nThe chance of a false-positive result in a standard two-step testing protocol is estimated to be about 1 in 250,000 in a low risk population.\nTesting post-exposure is recommended immediately and then at six weeks, three months, and six months.\nThe latest recommendations of the US [Centers for Disease Control and Prevention](https://bliptext.com/articles/centers-for-disease-control-and-prevention-cdc) (CDC) show that HIV testing must start with an [immunoassay](https://bliptext.com/articles/immunoassay) combination test for HIV-1 and HIV-2 [antibodies](https://bliptext.com/articles/antibody) and p24 [antigen](https://bliptext.com/articles/antigen).\nA negative result rules out HIV exposure, while a positive one must be followed by an HIV-1/2 antibody differentiation immunoassay to detect which antibodies are present.\nThis gives rise to four possible scenarios:\n# [A generalized graph of the relationship between HIV copies (viral load) and CD4 counts over the average course of untreated HIV infection; any particular individual's disease course may vary considerably. | upload.wikimedia.org/wikipedia/commons/0/0e/Hiv-timecourse///copy.svg]\n\n# Research\n[HIV/AIDS](https://bliptext.com/articles/hiv-aids) research includes all [medical research](https://bliptext.com/articles/medical-research) that attempts to prevent, treat, or cure [HIV/AIDS](https://bliptext.com/articles/hiv-aids), as well as fundamental research about the nature of HIV as an infectious agent and AIDS as the disease caused by HIV.\nMany governments and research institutions participate in HIV/AIDS research.\nThis research includes behavioral [health interventions](https://bliptext.com/articles/health-interventions), such as research into [sex education](https://bliptext.com/articles/sex-education), and [drug development](https://bliptext.com/articles/drug-development), such as research into [microbicides for sexually transmitted diseases](https://bliptext.com/articles/microbicides-for-sexually-transmitted-diseases), [HIV vaccines](https://bliptext.com/articles/hiv-vaccine), and [anti-retroviral drugs](https://bliptext.com/articles/antiretroviral-drug).\nOther medical research areas include the topics of [pre-exposure prophylaxis](https://bliptext.com/articles/pre-exposure-prophylaxis), [post-exposure prophylaxis](https://bliptext.com/articles/post-exposure-prophylaxis), [circumcision](https://bliptext.com/articles/circumcision-and-hiv), and [accelerated aging effects](https://bliptext.com/articles/biological-clock-aging).\n\n# Treatment and transmission\nThe management of HIV/AIDS typically involves the use of multiple [antiretroviral drugs](https://bliptext.com/articles/antiretroviral-drugs).\nIn many parts of the world, HIV has become a chronic condition, with progression to [AIDS](https://bliptext.com/articles/aids) increasingly rare.\n[HIV latency](https://bliptext.com/articles/hiv-latency) and the resulting [viral reservoir](https://bliptext.com/articles/viral-reservoir) in CD4+ T cells, dendritic cells, and macrophages is the main barrier to eradication of the virus.\nWhile HIV is highly virulent, transmission through sexual contact does not occur when an HIV-positive individual maintains a consistently undetectable [viral load](https://bliptext.com/articles/viral-load) (<50 copies/ml) due to antiretroviral treatment.\nThis concept was first proposed by the Swiss Federal Commission for AIDS/HIV in 2008 in what is known as the [Swiss Statement](https://bliptext.com/articles/swiss-statement).\nAlthough initially controversial, subsequent studies have confirmed that the risk of transmitting HIV through sex is effectively zero when the HIV-positive person has a consistently undetectable viral load, a concept now widely known as U=U, or \"Undetectable = Untransmittable.\"\nStudies that established the U=U principle include Opposites Attract, PARTNER 1, PARTNER 2 (which focused on male-male couples), and [HPTN052](https://bliptext.com/articles/hptn-052) (which focused on heterosexual couples).\nThese studies involved couples where one partner was HIV-positive and one was HIV-negative, and included regular HIV testing.\nAcross these four studies, a total of 4,097 couples participated from four continents, reporting 151,880 acts of condomless sex with zero phylogenetically-linked HIV transmissions when the positive partner had an undetectable viral load.\nFollowing these findings, the U=U consensus statement advocating the use of the term 'zero risk' was endorsed by numerous individuals and organizations, including the [CDC](https://bliptext.com/articles/cdc), the [British HIV Association](https://bliptext.com/articles/british-hiv-association), and [The Lancet](https://bliptext.com/articles/the-lancet) medical journal.\nAdditionally, reactivation of [herpes simplex virus-2](https://bliptext.com/articles/herpes-simplex-virus-2) (HSV-2) in individuals with [genital herpes](https://bliptext.com/articles/genital-herpes) is associated with an increase in [CCR-5](https://bliptext.com/articles/ccr5) enriched CD4+ T cells and inflammatory dendritic cells in the dermis of ulcerated genital skin, persisting even after ulcer healing.\nHIV's tropism for CCR-5 positive cells contributes to the two- to threefold increased risk of HIV acquisition in persons with genital herpes.\nNotably, daily antiviral medication, such as [acyclovir](https://bliptext.com/articles/acyclovir), does not reduce the subclinical post-reactivation inflammation and therefore does not decrease the risk of HIV acquisition.\n\n# History\n\n## Discovery\nThe first news story on \"an exotic new disease\" appeared May 18, 1981, in the gay newspaper [New York Native](https://bliptext.com/articles/new-york-native).\nAIDS was first clinically observed in 1981 in the United States.\nThe initial cases were a cluster of injection drug users and gay men with no known cause of impaired immunity who showed symptoms of [Pneumocystis](https://bliptext.com/articles/pneumocystis-jirovecii) pneumonia (PCP or PJP, the latter term recognizing that the causative agent is now called [Pneumocystis](https://bliptext.com/articles/pneumocystis-jirovecii) jirovecii), a rare opportunistic infection that was known to occur in people with very compromised immune systems.\nSoon thereafter, researchers at the [NYU School of Medicine](https://bliptext.com/articles/nyu-school-of-medicine) studied gay men developing a previously rare skin cancer called [Kaposi's sarcoma](https://bliptext.com/articles/kaposi-s-sarcoma) (KS).\nMany more cases of PJP and KS emerged, alerting U.S. [Centers for Disease Control and Prevention](https://bliptext.com/articles/centers-for-disease-control-and-prevention) (CDC) and a CDC task force was formed to monitor the outbreak.\nThe earliest retrospectively described case of AIDS is believed to have been in Norway beginning in 1966.\nIn the beginning, the CDC did not have an official name for the disease, often referring to it by way of the diseases that were associated with it, for example, [lymphadenopathy](https://bliptext.com/articles/lymphadenopathy), the disease after which the discoverers of HIV originally named the virus.\nThey also used Kaposi's Sarcoma and Opportunistic Infections, the name by which a task force had been set up in 1981.\nIn the general press, the term GRID, which stood for [gay-related immune deficiency](https://bliptext.com/articles/gay-related-immune-deficiency), had been coined.\nThe CDC, in search of a name and looking at the infected communities, coined \"the 4H disease\", as it seemed to single out homosexuals, heroin users, [hemophiliacs](https://bliptext.com/articles/haemophilia), and [Haitians](https://bliptext.com/articles/haiti).\nHowever, after determining that AIDS was not isolated to the [gay community](https://bliptext.com/articles/gay-community), it was realized that the term GRID was misleading and AIDS was introduced at a meeting in July 1982.\nBy September 1982 the CDC started using the name AIDS.\nIn 1983, two separate research groups led by American [Robert Gallo](https://bliptext.com/articles/robert-gallo) and French investigators Françoise Barré-Sinoussi and [Luc Montagnier](https://bliptext.com/articles/luc-montagnier) independently declared that a novel retrovirus may have been infecting AIDS patients, and published their findings in the same issue of the journal [Science](https://bliptext.com/articles/science-journal).\nGallo claimed that a virus his group had isolated from a person with AIDS was strikingly similar in [shape](https://bliptext.com/articles/virus-structure) to other [human T-lymphotropic viruses](https://bliptext.com/articles/human-t-lymphotropic-virus) (HTLVs) his group had been the first to isolate.\nGallo admitted in 1987 that the virus he claimed to have discovered in 1984 was in reality a virus sent to him from France the year before.\nGallo's group called their newly isolated virus HTLV-III.\nMontagnier's group isolated a virus from a patient presenting with swelling of the [lymph nodes](https://bliptext.com/articles/lymph-node) of the neck and [physical weakness](https://bliptext.com/articles/asthenia), two classic symptoms of primary HIV infection.\nContradicting the report from Gallo's group, Montagnier and his colleagues showed that core proteins of this virus were immunologically different from those of HTLV-I.\nMontagnier's group named their isolated virus lymphadenopathy-associated virus (LAV).\nAs these two viruses turned out to be the same, in 1986 LAV and HTLV-III were renamed HIV.\nAnother group working contemporaneously with the Montagnier and Gallo groups was that of [Jay A. Levy](https://bliptext.com/articles/jay-a-levy) at the [University of California, San Francisco](https://bliptext.com/articles/university-of-california-san-francisco).\nHe independently discovered the AIDS virus in 1983 and named it the AIDS associated retrovirus (ARV).\nThis virus was very different from the virus reported by the Montagnier and Gallo groups.\nThe ARV strains indicated, for the first time, the heterogeneity of HIV isolates and several of these remain classic examples of the AIDS virus found in the United States.\n\n## Origins\nBoth HIV-1 and HIV-2 are believed to have originated in non-human [primates](https://bliptext.com/articles/primate) in West-central Africa, and are believed to have transferred to humans (a process known as [zoonosis](https://bliptext.com/articles/zoonosis)) in the early 20th century.\nHIV-1 appears to have originated in southern [Cameroon](https://bliptext.com/articles/cameroon) through the evolution of SIVcpz, a [simian immunodeficiency virus](https://bliptext.com/articles/simian-immunodeficiency-virus) (SIV) that infects wild [chimpanzees](https://bliptext.com/articles/common-chimpanzee) (HIV-1 descends from the SIVcpz endemic in the chimpanzee subspecies [Pan troglodytes troglodytes](https://bliptext.com/articles/central-chimpanzee)).\nThe closest relative of HIV-2 is SIVsmm, a virus of the [sooty mangabey](https://bliptext.com/articles/sooty-mangabey) (Cercocebus atys atys), an [Old World monkey](https://bliptext.com/articles/old-world-monkey) living in littoral West Africa (from southern [Senegal](https://bliptext.com/articles/senegal) to western [Côte d'Ivoire](https://bliptext.com/articles/ivory-coast)).\n[New World monkeys](https://bliptext.com/articles/new-world-monkey) such as the [owl monkey](https://bliptext.com/articles/night-monkey) are resistant to HIV-1 infection, possibly because of a [genomic fusion](https://bliptext.com/articles/fusion-gene) of two viral resistance genes.\nHIV-1 is thought to have jumped the species barrier on at least three separate occasions, giving rise to the three groups of the virus, M, N, and O.\nThere is evidence that humans who participate in [bushmeat](https://bliptext.com/articles/bushmeat) activities, either as hunters or as [bushmeat](https://bliptext.com/articles/bushmeat) vendors, commonly acquire SIV.\nHowever, SIV is a weak virus, and it is typically suppressed by the human immune system within weeks of infection.\nIt is thought that several transmissions of the virus from individual to individual in quick succession are necessary to allow it enough time to mutate into HIV.\nFurthermore, due to its relatively low person-to-person transmission rate, it can only spread throughout the population in the presence of one or more high-risk transmission channels, which are thought to have been absent in Africa prior to the 20th century.\nSpecific proposed high-risk transmission channels, allowing the virus to adapt to humans and spread throughout the society, depend on the proposed timing of the animal-to-human crossing.\nGenetic studies of the virus suggest that the most recent common ancestor of the HIV-1 M group dates back to c. 1910.\nProponents of this dating link the HIV epidemic with the emergence of [colonialism](https://bliptext.com/articles/colonialism) and growth of large colonial African cities, leading to social changes, including different patterns of sexual contact (especially multiple, concurrent partnerships), the spread of [prostitution](https://bliptext.com/articles/prostitution), and the concomitant high frequency of [genital ulcer](https://bliptext.com/articles/genital-ulcer) diseases (such as [syphilis](https://bliptext.com/articles/syphilis)) in nascent colonial cities.\nWhile transmission rates of HIV during vaginal intercourse are typically low, they are increased manyfold if one of the partners has a [sexually transmitted infection](https://bliptext.com/articles/sexually-transmitted-disease) resulting in genital ulcers.\nEarly 1900s colonial cities were notable for their high prevalence of prostitution and genital ulcers to the degree that as of 1928 as many as 45% of female residents of eastern [Leopoldville (currently Kinshasa)](https://bliptext.com/articles/kinshasa) were thought to have been prostitutes and as of 1933 around 15% of all residents of the same city were infected by one of the forms of [syphilis](https://bliptext.com/articles/syphilis).\nThe earliest, well-documented case of HIV in a human dates back to 1959 in the [Belgian Congo](https://bliptext.com/articles/belgian-congo).\nThe virus may have been present in the United States as early as the mid- to late 1960s, as a sixteen-year-old male named [Robert Rayford](https://bliptext.com/articles/robert-rayford) presented with symptoms in 1966 and died in 1969.\nAn alternative and likely complementary hypothesis points to the widespread use of unsafe medical practices in Africa during years following World War II, such as unsterile reuse of single-use syringes during mass vaccination, antibiotic, and anti-malaria treatment campaigns.\nResearch on the timing of most recent common ancestor for HIV-1 groups M and O, as well as on HIV-2 groups A and B, indicates that SIV has given rise to transmissible HIV lineages throughout the twentieth century.\nThe dispersed timing of these transmissions to humans implies that no single external factor is needed to explain the cross-species transmission of HIV.\nThis observation is consistent with both of the two prevailing views of the origin of the HIV epidemics, namely SIV transmission to humans during the slaughter or butchering of infected primates, and the colonial expansion of sub-Saharan African cities.\n# [Left to right: the African green monkey source of SIV, the sooty mangabey source of HIV-2, and the chimpanzee source of HIV-1 | upload.wikimedia.org/wikipedia/commons/9/93/SIV///primates.jpg]","revisionCount":1},"hasMore":false,"nextCursor":null}