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{{short description|Human retrovirus, cause of AIDS}}
{{cs1 config|name-list-style=vanc}}
{{About|the virus|the infection caused by the virus|HIV/AIDS|other uses}}
{{Redirect|AIDS virus|the computer virus|AIDS (computer virus)}}
{{pp|small=yes}}
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{{Good article}}
{{Use mdy dates|date=June 2013}}
{{Paraphyletic group
| name = Human immunodeficiency viruses
| image = HIV-budding-Color.jpg
| 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.
| image_caption = [[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.
| auto = virus
| parent = Lentivirus
| includes = 
*''[[Subtypes of HIV#HIV-1|Human immunodeficiency virus 1]]''
*''[[Subtypes of HIV#HIV-2|Human immunodeficiency virus 2]]''
| excludes_text = Other lentiviruses
| excludes = 
*''[[Bovine immunodeficiency virus]]''
*''[[Caprine arthritis encephalitis virus]]''
*''[[Equine infectious anemia virus]]''
*''[[Feline immunodeficiency virus]]''
*''[[Jembrana disease virus]]''
*''[[Puma lentivirus]]''
*''[[Simian immunodeficiency virus]]''
*''[[Visna-maedi virus]]''
}}

The '''human immunodeficiency viruses''' ('''HIV''') are two species of ''[[Lentivirus]]'' (a subgroup of [[retrovirus]]) that infect humans. Over time, they cause [[AIDS|acquired immunodeficiency syndrome]] (AIDS),<ref name="pmid8493571">{{cite journal | vauthors = Weiss RA | title = How does HIV cause AIDS? | journal = Science | volume = 260 | issue = 5112 | pages = 1273–9 | date = May 1993 | pmid = 8493571 | doi = 10.1126/science.8493571 | bibcode = 1993Sci...260.1273W }}</ref><ref name="pmid18947296">{{cite journal | vauthors = Douek DC, Roederer M, Koup RA | title = Emerging Concepts in the Immunopathogenesis of AIDS | journal = Annual Review of Medicine | volume = 60 | pages = 471–84 | year = 2009 | pmid = 18947296 | pmc = 2716400 | doi = 10.1146/annurev.med.60.041807.123549 }}</ref> a condition in which progressive failure of the [[immune system]] allows life-threatening [[opportunistic infection]]s and [[cancer]]s to thrive.<ref name="pmid27611681">{{cite journal | vauthors = Powell MK, Benková K, Selinger P, Dogoši M, Kinkorová Luňáčková I, Koutníková H, Laštíková J, Roubíčková A, Špůrková Z, Laclová L, Eis V, Šach J, Heneberg P | title = Opportunistic Infections in HIV-Infected Patients Differ Strongly in Frequencies and Spectra between Patients with Low CD4+ Cell Counts Examined Postmortem and Compensated Patients Examined Antemortem Irrespective of the HAART Era | journal = PLOS ONE | volume = 11 | issue = 9 | pages = e0162704 | year = 2016 | pmid = 27611681 | pmc = 5017746 | doi = 10.1371/journal.pone.0162704 | bibcode = 2016PLoSO..1162704P | doi-access = free }}</ref> Without treatment, the average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the [[Subtypes of HIV|HIV subtype]].<ref name=UNAIDS2007>{{cite web| date = December 2007| title = 2007 AIDS epidemic update| url=https://data.unaids.org/pub/epislides/2007/2007_epiupdate_en.pdf#page16 | author1 = UNAIDS| author2 = WHO | page=16}}</ref>

In most cases, HIV is a [[sexually transmitted infection]] and [[HIV/AIDS#Transmission|occurs]] by contact with or transfer of [[blood]], [[pre-ejaculate]], [[semen]], and [[Vaginal lubrication|vaginal fluids]].<ref name="PARTNER2-2019">{{cite journal |display-authors=6 |vauthors=Rodger AJ, Cambiano V, Bruun T, Vernazza P, Collins S, Degen O, Corbelli GM, Estrada V, Geretti AM, Beloukas A, Raben D, Coll P, Antinori A, Nwokolo N, Rieger A, Prins JM, Blaxhult A, Weber R, Van Eeden A, Brockmeyer NH, Clarke A, Del Romero Guerrero J, Raffi F, Bogner JR, Wandeler G, Gerstoft J, Gutiérrez F, Brinkman K, Kitchen M, Ostergaard L, Leon A, Ristola M, Jessen H, Stellbrink HJ, Phillips AN, Lundgren J |date=June 2019 |title=Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study |journal=Lancet |volume=393 |issue=10189 |pages=2428–2438 |doi=10.1016/S0140-6736(19)30418-0 |pmc=6584382 |pmid=31056293 |doi-access=free}}</ref><ref name="Fauci-JAMA">{{cite journal |author-link3=Anthony S. Fauci |vauthors=Eisinger RW, Dieffenbach CW, Fauci AS |date=February 2019 |title=HIV Viral Load and Transmissibility of HIV Infection: Undetectable Equals Untransmittable |journal=JAMA |volume=321 |issue=5 |pages=451–452 |doi=10.1001/jama.2018.21167 |pmid=30629090 |s2cid=58599661}}</ref> Non-sexual transmission can occur from an infected mother to her infant during [[pregnancy]], during [[childbirth]] by exposure to her blood or vaginal fluid, and through [[breast milk]].<ref>{{cite journal | vauthors = Mabuka J, Nduati R, Odem-Davis K, Peterson D, Overbaugh J | title = HIV-Specific Antibodies Capable of ADCC Are Common in Breastmilk and Are Associated with Reduced Risk of Transmission in Women with High Viral Loads | journal = PLOS Pathogens | volume = 8 | issue = 6 | pages = e1002739 | year = 2012 | pmid = 22719248 | pmc = 3375288 | doi = 10.1371/journal.ppat.1002739 | veditors = Desrosiers RC | doi-access = free }}</ref><ref>{{Cite book |title=Anthropology and public health : bridging differences in culture and society |date=2009 |publisher=Oxford University Press | veditors = Hahn RA, Inhorn MC |isbn=978-0-19-537464-3 |edition=2nd |location=Oxford |pages = 449 |oclc=192042314}}</ref><ref name="Mead">{{cite journal |author = Mead MN |title = Contaminants in human milk: weighing the risks against the benefits of breastfeeding |journal = Environmental Health Perspectives |volume = 116 |issue = 10 |pages = A426–34 |year = 2008 |pmid = 18941560 |pmc = 2569122 |doi = 10.1289/ehp.116-a426 |url = http://www.ehponline.org/members/2008/116-10/focus.html |url-status = dead |archive-url = https://web.archive.org/web/20081106182431/http://www.ehponline.org/members/2008/116-10/focus.html |archive-date = 6 November 2008 |df = dmy-all }}</ref><ref>{{citation-attribution|1={{cite web|url=https://www.hiv.gov/hiv-basics/hiv-prevention/reducing-mother-to-child-risk/preventing-mother-to-child-transmission-of-hiv|title=Preventing Mother-to-Child Transmission of HIV|website=HIV.gov|access-date=2017-12-08|date=2017-05-15}}}}</ref> Within these bodily fluids, HIV is present as both free [[virus]] particles and virus within infected [[White blood cell|immune cells]].
Research 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 monitoring for HIV|viral load]].<ref name = PARTNER2-2019 /><ref name = Fauci-JAMA />

HIV infects vital cells in the human immune system, such as [[T helper cell|helper T cells]] (specifically [[CD4]]<SUP>+</SUP> T cells), [[macrophage]]s, and [[dendritic cell]]s.<ref>{{cite journal | vauthors = Cunningham AL, Donaghy H, Harman AN, Kim M, Turville SG | title = Manipulation of dendritic cell function by viruses | journal = Current Opinion in Microbiology | volume = 13 | issue = 4 | pages = 524–9 | date = August 2010 | pmid = 20598938 | doi = 10.1016/j.mib.2010.06.002 }}</ref> HIV infection leads to low levels of CD4<SUP>+</SUP> T cells through a number of mechanisms, including [[pyroptosis]] of abortively infected T cells,<ref name="pmid24356306">{{cite journal | vauthors = Doitsh G, Galloway NL, Geng X, Yang Z, Monroe KM, Zepeda O, Hunt PW, Hatano H, Sowinski S, Muñoz-Arias I, Greene WC | display-authors = 6 | title = Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection | journal = Nature | volume = 505 | issue = 7484 | pages = 509–14 | date = January 2014 | pmid = 24356306 | pmc = 4047036 | doi = 10.1038/nature12940 | bibcode = 2014Natur.505..509D }}</ref> [[apoptosis]] of uninfected bystander cells,<ref>{{cite journal | vauthors = Garg H, Mohl J, Joshi A | title = HIV-1 induced bystander apoptosis | journal = Viruses | volume = 4 | issue = 11 | pages = 3020–43 | date = November 2012 | pmid = 23202514 | pmc = 3509682 | doi = 10.3390/v4113020 | doi-access = free }}</ref> direct viral killing of infected cells, and killing of infected CD4<SUP>+</SUP> T cells by [[CD8 cytotoxic lymphocyte|CD8<SUP>+</SUP> cytotoxic lymphocyte]]s that recognize infected cells.<ref>{{cite book | vauthors = Kumar V |title=Robbins Basic Pathology |year=2012 |isbn=978-1-4557-3787-1 |pages = 147 |publisher=Elsevier Health Sciences |url=https://books.google.com/books?id=jheBzf17C7YC&pg=PA147 |edition=9th }}</ref> When CD4<SUP>+</SUP> T cell numbers decline below a critical level, [[cell-mediated immunity]] is lost, and the body becomes progressively more susceptible to opportunistic infections, leading to the development of AIDS.
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==Virology==
{| class="wikitable" style="float:center; font-size:85%; margin-left:15px;"
|+Comparison of HIV species
|-
! Species !! [[Virulence]] !! [[Infectivity]] !! Prevalence !! Inferred origin
|-
! HIV-1
| High || High || Global || [[Common chimpanzee]]
|-
! HIV-2
| Lower || Low || West Africa || [[Sooty mangabey]]
|}
===Classification===
{{see also|Subtypes of HIV}}
HIV is a member of the [[genus]] ''[[Lentivirus]]'',<ref name="ICTV61.0.6">{{cite web |author=International Committee on Taxonomy of Viruses |author-link=International Committee on Taxonomy of Viruses |year=2002 |title=61.0.6. Lentivirus |url=https://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/61060000.htm |url-status=usurped |archive-url=https://web.archive.org/web/20061014181406/https://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/61060000.htm |archive-date=October 14, 2006 |access-date=February 28, 2006 |publisher=[[National Institutes of Health]]}}</ref> part of the family ''[[Retroviridae]]''.<ref name="ICTV61.">{{cite web |author=International Committee on Taxonomy of Viruses |year=2002 |title=61. Retroviridae |url=https://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/61000000.htm |url-status=usurped |archive-url=https://web.archive.org/web/20061002234645/https://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/61000000.htm |archive-date=October 2, 2006 |access-date=February 28, 2006 |publisher=National Institutes of Health}}</ref> Lentiviruses have many [[morphology (biology)|morphologies]] and [[biology|biological]] properties in common. Many species are infected by lentiviruses, which are characteristically responsible for long-duration illnesses with a long [[incubation period]].<ref name=Levy>{{cite journal | vauthors = Levy JA | title = HIV pathogenesis and long-term survival | journal = AIDS | volume = 7 | issue = 11 | pages = 1401–10 | date = November 1993 | pmid = 8280406 | doi = 10.1097/00002030-199311000-00001 }}</ref> Lentiviruses are transmitted as [[single-stranded]], positive-[[Sense (molecular biology)|sense]], [[Viral envelope|enveloped]] [[RNA virus]]es. Upon entry into the target cell, the viral [[RNA]] [[genome]] is converted (reverse transcribed) into double-stranded [[DNA]] by a virally encoded enzyme, [[reverse transcriptase]], that is transported along with the viral genome in the virus particle. The resulting viral DNA is then imported into the [[cell nucleus]] and integrated into the cellular DNA by a virally encoded enzyme, [[integrase]], and host [[Cofactor (biochemistry)|co-factors]].<ref name="JASmith">{{cite journal | vauthors = Smith JA, Daniel R | title = Following the path of the virus: the exploitation of host DNA repair mechanisms by retroviruses | journal = ACS Chemical Biology | volume = 1 | issue = 4 | pages = 217–26 | date = May 2006 | pmid = 17163676 | doi = 10.1021/cb600131q }}</ref> Once integrated, the virus may become [[Virus latency|latent]], allowing the virus and its host cell to avoid detection by the immune system, for an indeterminate amount of time.<ref name="HIV Latency">{{cite journal | vauthors = Siliciano RF, Greene WC | title = HIV latency | journal = Cold Spring Harbor Perspectives in Medicine | volume = 1 | issue = 1 | pages = a007096 | date = September 2011 | pmid = 22229121 | pmc = 3234450 | doi = 10.1101/cshperspect.a007096 }}</ref> The 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. Alternatively, the integrated viral DNA may be [[Transcription (genetics)|transcribed]], 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.

Two types of HIV have been characterized: HIV-1 and HIV-2. HIV-1 is the virus that was initially discovered and termed both lymphadenopathy associated virus (LAV) and human T-lymphotropic virus 3 (HTLV-III). HIV-1 is more [[virulence|virulent]] and more [[infectivity|infective]] than HIV-2,<ref>{{cite journal | vauthors = Gilbert PB, McKeague IW, Eisen G, Mullins C, Guéye-NDiaye A, Mboup S, Kanki PJ | title = Comparison of HIV-1 and HIV-2 infectivity from a prospective cohort study in Senegal | journal = Statistics in Medicine | volume = 22 | issue = 4 | pages = 573–593 | date = February 28, 2003 | pmid = 12590415 | doi = 10.1002/sim.1342 | s2cid = 28523977 }}</ref> and is the cause of the majority of HIV infections globally. The lower infectivity of HIV-2, compared to HIV-1, implies that fewer of those exposed to HIV-2 will be infected per exposure. Due to its relatively poor capacity for transmission, HIV-2 is largely confined to [[West Africa]].<ref name=Reeves>{{cite journal | vauthors = Reeves JD, Doms RW | title = Human Immunodeficiency Virus Type 2 | journal = [[Journal of General Virology]] | volume = 83 | issue = Pt 6 | pages = 1253–65 | year = 2002 | pmid = 12029140 | doi = 10.1099/0022-1317-83-6-1253 | doi-access = free }}</ref>

===Structure and genome===
{{Main|Structure and genome of HIV}}
[[File:HI-virion-structure en.svg|thumb|upright=1.35|Diagram of the HIV virion]]
HIV is similar in structure to other retroviruses. It is roughly spherical<ref name=McGovern>{{cite journal | vauthors = McGovern SL, Caselli E, Grigorieff N, Shoichet BK | title = A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening | journal = Journal of Medicinal Chemistry | volume = 45 | issue = 8 | pages = 1712–22 | year = 2002 | pmid = 11931626 | doi = 10.1021/jm010533y | hdl = 11380/977912 }}</ref> with a diameter of about 120&nbsp;[[Nanometre|nm]], around 100,000&nbsp;times smaller in volume than a [[red blood cell]].<ref name=Microbiology3>Compared with overview in: {{cite book | vauthors = Fisher B, Harvey RP, Champe PC |title=Lippincott's Illustrated Reviews: Microbiology |publisher=Lippincott Williams & Wilkins |location=Hagerstown, MD |year=2007 |pages = 3 |isbn=978-0-7817-8215-9 }}</ref> It is composed of two copies of positive-[[Sense (molecular biology)|sense]] [[single-stranded]] [[RNA]] that codes for the virus' nine [[gene]]s enclosed by a conical [[capsid]] composed of 2,000 copies of the viral protein [[P24 capsid protein|p24]].<ref name=compendia>{{cite book | author = Various | year = 2008 | title = HIV Sequence Compendium 2008 Introduction | url = http://www.hiv.lanl.gov/content/sequence/HIV/COMPENDIUM/2008/frontmatter.pdf | access-date = March 31, 2009 }}</ref> The single-stranded RNA is tightly bound to nucleocapsid proteins, p7, and enzymes needed for the development of the virion such as [[reverse transcriptase]], [[protease]]s, [[ribonuclease]] and [[integrase]]. A matrix composed of the viral protein p17 surrounds the capsid ensuring the integrity of the virion particle.<ref name=compendia />

This is, in turn, surrounded by the [[viral envelope]], that is composed of the [[lipid bilayer]] taken from the membrane of a human host cell when the newly formed virus particle buds from the cell. The viral envelope contains proteins from the host cell and relatively few copies of the HIV envelope protein,<ref name=compendia /> which consists of a cap made of three molecules known as [[gp120|glycoprotein (gp) 120]], and a stem consisting of three [[gp41]] molecules that anchor the structure into the viral envelope.<ref name=Chan>{{cite journal | vauthors = Chan DC, Fass D, Berger JM, Kim PS | title = Core structure of gp41 from the HIV envelope glycoprotein | journal = Cell | volume = 89 | issue = 2 | pages = 263–73 | date = April 1997 | pmid = 9108481 | doi = 10.1016/S0092-8674(00)80205-6 | url = http://www.its.caltech.edu/~chanlab/PDFs/Chan_Cell_1997.pdf | s2cid = 4518241 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Klein JS, Bjorkman PJ | title = Few and far between: how HIV may be evading antibody avidity | journal = PLOS Pathogens | volume = 6 | issue = 5 | pages = e1000908 | date = May 2010 | pmid = 20523901 | pmc = 2877745 | doi = 10.1371/journal.ppat.1000908 | doi-access = free }}</ref> The envelope protein, encoded by the HIV [[Env (gene)|''env'']] gene, allows the virus to attach to target cells and fuse the viral envelope with the target [[cell membrane|cell's membrane]] releasing the viral contents into the cell and initiating the infectious cycle.<ref name=Chan />

[[File:Protein Structure Diagram of Fusion Peptide Epitope on HIV Spike (41863579304).jpg|thumb|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]]
As the sole viral protein on the surface of the virus, the envelope protein is a major target for [[HIV vaccine]] efforts.<ref name="nih1998">{{cite press release | author=National Institute of Health | title=Crystal structure of key HIV protein reveals new prevention, treatment targets | date=June 17, 1998 |url=http://www3.niaid.nih.gov/news/newsreleases/1998/hivprotein.htm | access-date = September 14, 2006 |archive-url=https://web.archive.org/web/20060219112450/http://www3.niaid.nih.gov/news/newsreleases/1998/hivprotein.htm |archive-date=February 19, 2006}}</ref> Over half of the mass of the trimeric envelope spike is N-linked [[glycan]]s. The density is high as the glycans shield the underlying viral protein from neutralisation by antibodies. This 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.<ref>{{cite journal | vauthors = Behrens AJ, Vasiljevic S, Pritchard LK, Harvey DJ, Andev RS, Krumm SA, Struwe WB, Cupo A, Kumar A, Zitzmann N, Seabright GE, Kramer HB, Spencer DI, Royle L, Lee JH, Klasse PJ, Burton DR, Wilson IA, Ward AB, Sanders RW, Moore JP, Doores KJ, Crispin M | display-authors = 6 | title = Composition and Antigenic Effects of Individual Glycan Sites of a Trimeric HIV-1 Envelope Glycoprotein | journal = Cell Reports | volume = 14 | issue = 11 | pages = 2695–706 | date = March 2016 | pmid = 26972002 | pmc = 4805854 | doi = 10.1016/j.celrep.2016.02.058 }}</ref><ref>{{cite journal | vauthors = Pritchard LK, Spencer DI, Royle L, Bonomelli C, Seabright GE, Behrens AJ, Kulp DW, Menis S, Krumm SA, Dunlop DC, Crispin DJ, Bowden TA, Scanlan CN, Ward AB, Schief WR, Doores KJ, Crispin M | display-authors = 6 | title = Glycan clustering stabilizes the mannose patch of HIV-1 and preserves vulnerability to broadly neutralizing antibodies | journal = Nature Communications | volume = 6 | pages = 7479 | date = June 2015 | pmid = 26105115 | pmc = 4500839 | doi = 10.1038/ncomms8479 | bibcode = 2015NatCo...6.7479P }}</ref> The 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.<ref>{{cite journal | vauthors = Pritchard LK, Harvey DJ, Bonomelli C, Crispin M, Doores KJ | title = Cell- and Protein-Directed Glycosylation of Native Cleaved HIV-1 Envelope | journal = Journal of Virology | volume = 89 | issue = 17 | pages = 8932–44 | date = September 2015 | pmid = 26085151 | pmc = 4524065 | doi = 10.1128/JVI.01190-15 }}</ref> The 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.<ref>{{cite journal | vauthors = Crispin M, Doores KJ | title = Targeting host-derived glycans on enveloped viruses for antibody-based vaccine design | journal = Current Opinion in Virology | volume = 11 | pages = 63–9 | date = April 2015 | pmid = 25747313 | pmc = 4827424 | doi = 10.1016/j.coviro.2015.02.002 | author-link2 = Katie Doores }}</ref>

The molecular structure of the viral spike has now been determined by [[X-ray crystallography]]<ref>{{cite journal | vauthors = Julien JP, Cupo A, Sok D, Stanfield RL, Lyumkis D, Deller MC, Klasse PJ, Burton DR, Sanders RW, Moore JP, Ward AB, Wilson IA | display-authors = 6 | title = Crystal structure of a soluble cleaved HIV-1 envelope trimer | journal = Science | volume = 342 | issue = 6165 | pages = 1477–83 | date = December 2013 | pmid = 24179159 | pmc = 3886632 | doi = 10.1126/science.1245625 | bibcode = 2013Sci...342.1477J }}</ref> and [[cryogenic electron microscopy]].<ref>{{cite journal | vauthors = Lyumkis D, Julien JP, de Val N, Cupo A, Potter CS, Klasse PJ, Burton DR, Sanders RW, Moore JP, Carragher B, Wilson IA, Ward AB | display-authors = 6 | title = Cryo-EM structure of a fully glycosylated soluble cleaved HIV-1 envelope trimer | journal = Science | volume = 342 | issue = 6165 | pages = 1484–90 | date = December 2013 | pmid = 24179160 | pmc = 3954647 | doi = 10.1126/science.1245627 | bibcode = 2013Sci...342.1484L }}</ref> These advances in structural biology were made possible due to the development of stable [[Recombinant organism|recombinant]] forms of the viral spike by the introduction of an intersubunit [[disulphide bond]] and an [[isoleucine]] to [[proline]] [[mutation]] ([[radical replacement]] of an amino acid) in gp41.<ref>{{cite journal | vauthors = Sanders RW, Derking R, Cupo A, Julien JP, Yasmeen A, de Val N, Kim HJ, Blattner C, de la Peña AT, Korzun J, Golabek M, de Los Reyes K, Ketas TJ, van Gils MJ, King CR, Wilson IA, Ward AB, Klasse PJ, Moore JP | display-authors = 6 | title = A next-generation cleaved, soluble HIV-1 Env trimer, BG505 SOSIP.664 gp140, expresses multiple epitopes for broadly neutralizing but not non-neutralizing antibodies | journal = PLOS Pathogens | volume = 9 | issue = 9 | pages = e1003618 | date = September 2013 | pmid = 24068931 | pmc = 3777863 | doi = 10.1371/journal.ppat.1003618 | doi-access = free }}</ref> The so-called SOSIP [[Trimer (chemistry)|trimers]] 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.<ref>{{cite journal | vauthors = Pritchard LK, Vasiljevic S, Ozorowski G, Seabright GE, Cupo A, Ringe R, Kim HJ, Sanders RW, Doores KJ, Burton DR, Wilson IA, Ward AB, Moore JP, Crispin M | display-authors = 6 | title = Structural Constraints Determine the Glycosylation of HIV-1 Envelope Trimers | journal = Cell Reports | volume = 11 | issue = 10 | pages = 1604–13 | date = June 2015 | pmid = 26051934 | pmc = 4555872 | doi = 10.1016/j.celrep.2015.05.017 }}</ref> Recombinant trimeric viral spikes are promising vaccine candidates as they display less non-neutralising [[epitope]]s than recombinant monomeric gp120, which act to suppress the immune response to target epitopes.<ref>{{cite journal | vauthors = de Taeye SW, Ozorowski G, Torrents de la Peña A, Guttman M, Julien JP, van den Kerkhof TL, Burger JA, Pritchard LK, Pugach P, Yasmeen A, Crampton J, Hu J, Bontjer I, Torres JL, Arendt H, DeStefano J, Koff WC, Schuitemaker H, Eggink D, Berkhout B, Dean H, LaBranche C, Crotty S, Crispin M, Montefiori DC, Klasse PJ, Lee KK, Moore JP, Wilson IA, Ward AB, Sanders RW | display-authors = 6 | title = Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes | journal = Cell | volume = 163 | issue = 7 | pages = 1702–15 | date = December 2015 | pmid = 26687358 | pmc = 4732737 | doi = 10.1016/j.cell.2015.11.056 }}</ref> 
[[File:HIV-genome.png|thumb|upright=2.05|Structure of the RNA genome of HIV-1]]
The RNA genome consists of at least seven structural landmarks ([[Long terminal repeat|LTR]], [[Trans-activation response element (TAR)|TAR]], [[HIV Rev response element|RRE]], 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. Three of these genes, ''gag'', ''pol'', and ''env'', contain information needed to make the structural proteins for new virus particles.<ref name=compendia /> For example, ''env'' codes for a protein called gp160 that is cut in two by a cellular protease to form gp120 and gp41. The 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.<ref name=compendia />

The two ''[[Tat (HIV)|tat]]'' proteins (p16 and p14) are [[Activator (genetics)|transcriptional transactivators]] for the LTR [[Promoter (genetics)|promoter]] acting by binding the TAR RNA element. The TAR may also be processed into [[microRNA]]s that regulate the [[apoptosis]] genes ''[[ERCC1]]'' and ''[[IER3]]''.<ref name="pmid18299284">{{cite journal | vauthors = Ouellet DL, Plante I, Landry P, Barat C, Janelle ME, Flamand L, Tremblay MJ, Provost P | title = Identification of functional microRNAs released through asymmetrical processing of HIV-1 TAR element | journal = Nucleic Acids Research | volume = 36 | issue = 7 | pages = 2353–65 | date = April 2008 | pmid = 18299284 | pmc = 2367715 | doi = 10.1093/nar/gkn076 }}</ref><ref name="pmid19220914">{{cite journal | vauthors = Klase Z, Winograd R, Davis J, Carpio L, Hildreth R, Heydarian M, Fu S, McCaffrey T, Meiri E, Ayash-Rashkovsky M, Gilad S, Bentwich Z, Kashanchi F | title = HIV-1 TAR miRNA protects against apoptosis by altering cellular gene expression | journal = Retrovirology | volume = 6 | issue = 1 | pages =  18 | year = 2009 | pmid = 19220914 | pmc = 2654423 | doi = 10.1186/1742-4690-6-18 | doi-access = free }}</ref> The [[Rev (HIV)|''rev'']] protein (p19) is involved in shuttling RNAs from the nucleus and the cytoplasm by binding to the [[HIV Rev response element|RRE]] RNA element. The ''vif'' protein (p23) prevents the action of [[APOBEC3G]] (a cellular protein that [[Deamination|deaminates]] [[cytidine]] to [[uridine]] in the single-stranded viral DNA and/or interferes with reverse transcription<ref>{{cite journal | vauthors = Vasudevan AA, Smits SH, Höppner A, Häussinger D, Koenig BW, Münk C | title = Structural features of antiviral DNA cytidine deaminases | journal = [[Biological Chemistry (journal)|Biological Chemistry]] | volume = 394 | issue = 11 | pages = 1357–70 | date = Nov 2013 | pmid = 23787464 | doi = 10.1515/hsz-2013-0165 | s2cid = 4151961 | url = http://juser.fz-juelich.de/search?p=id:%22FZJ-2013-05757%22 | type = Submitted manuscript }}</ref>).  The ''[[vpr]]'' protein (p14) arrests [[cell division]] at [[G2/M checkpoint|G2/M]]. The ''nef'' protein (p27) down-regulates [[CD4]] (the major viral receptor), as well as the [[MHC class I]] and [[MHC class II|class II]] molecules.<ref name="pmid2014052">{{cite journal | vauthors = Garcia JV, Miller AD | title = Serine phosphorylation-independent downregulation of cell-surface CD4 by nef | journal = Nature | volume = 350 | issue = 6318 | pages = 508–11 | date = April 1991 | pmid = 2014052 | doi = 10.1038/350508a0 | bibcode = 1991Natur.350..508G | s2cid = 1628392 }}</ref><ref name="pmid8612235">{{cite journal | vauthors = Schwartz O, Maréchal V, Le Gall S, Lemonnier F, Heard JM | title = Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein | journal = Nature Medicine | volume = 2 | issue = 3 | pages = 338–42 | date = March 1996 | pmid = 8612235 | doi = 10.1038/nm0396-338 | s2cid = 7461342 }}</ref><ref name="pmid11593029">{{cite journal | vauthors = Stumptner-Cuvelette P, Morchoisne S, Dugast M, Le Gall S, Raposo G, Schwartz O, Benaroch P | title = HIV-1 Nef impairs MHC class II antigen presentation and surface expression | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 21 | pages = 12144–9 | date = October 2001 | pmid = 11593029 | pmc = 59782 | doi = 10.1073/pnas.221256498 | bibcode = 2001PNAS...9812144S | doi-access = free }}</ref>

''Nef'' also interacts with [[SH3 domain]]s. The ''vpu'' protein (p16) influences the release of new virus particles from infected cells.<ref name=compendia /> The ends of each strand of HIV RNA contain an RNA sequence called a [[long terminal repeat]] (LTR). Regions 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. The [[Retroviral Psi packaging element|Psi element]] is involved in viral genome packaging and recognized by [[Group-specific antigen|''gag'']] and [[Rev (HIV)|''rev'']] proteins. The SLIP element ({{DNA sequence|TTTTTT}}) is involved in the [[Translational frameshift|frameshift]] in the ''gag''-''pol'' [[reading frame]] required to make functional ''pol''.<ref name=compendia />

===Tropism===
{{Main|HIV tropism}}
[[File:HIV Mature and Immature.PNG|thumb|right|Diagram of the immature and mature forms of HIV]]
The term [[viral tropism]] refers to the cell types a virus infects. HIV can infect a variety of immune cells such as [[Helper T cell|CD4<SUP>+</SUP> T cells]], [[macrophage]]s, and [[microglial cell]]s. HIV-1 entry to macrophages and CD4<SUP>+</SUP> 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]] [[co-receptor]]s.<ref name=Chan /><ref>{{cite journal | vauthors = Arrildt KT, Joseph SB, Swanstrom R | title = The HIV-1 env protein: a coat of many colors | journal = Current HIV/AIDS Reports | volume = 9 | issue = 1 | pages = 52–63 | date = March 2012 | pmid = 22237899 | pmc = 3658113 | doi = 10.1007/s11904-011-0107-3 }}</ref>

Macrophage-tropic (M-tropic) strains of HIV-1, or non-[[syncytia]]-inducing strains (NSI; now called R5 viruses<ref name="pmid9440686">{{cite journal | vauthors = Berger EA, Doms RW, Fenyö EM, Korber BT, Littman DR, Moore JP, Sattentau QJ, Schuitemaker H, Sodroski J, Weiss RA | title = A new classification for HIV-1 | journal = Nature | volume = 391 | issue = 6664 | pages =  240 | year = 1998 | pmid = 9440686 | doi = 10.1038/34571 | bibcode = 1998Natur.391..240B | s2cid = 2159146 | doi-access = free }}</ref>) use the ''β''-chemokine receptor, [[CCR5]], for entry and are thus able to replicate in both macrophages and CD4<SUP>+</SUP> T cells.<ref name=Coakley>{{cite journal | vauthors = Coakley E, Petropoulos CJ, Whitcomb JM | title = Assessing ch vbgemokine co-receptor usage in HIV | journal = Current Opinion in Infectious Diseases | volume = 18 | issue = 1 | pages = 9–15 | year = 2005 | pmid = 15647694 | doi = 10.1097/00001432-200502000-00003 | s2cid = 30923492 }}</ref> This CCR5 co-receptor is used by almost all primary HIV-1 isolates regardless of viral genetic subtype. Indeed, macrophages play a key role in several critical aspects of HIV infection. They appear to be the first cells infected by HIV and perhaps the source of HIV production when CD4<SUP>+</SUP> cells become depleted in the patient. Macrophages and microglial cells are the cells infected by HIV in the [[central nervous system]]. In the [[tonsil]]s and [[adenoids]] of HIV-infected patients, macrophages fuse into multinucleated [[giant cell]]s that produce huge amounts of virus.

T-tropic strains of HIV-1, or [[syncytia]]-inducing strains (SI; now called X4 viruses<ref name="pmid9440686" />) replicate in primary CD4<SUP>+</SUP> T cells as well as in macrophages and use the ''α''-chemokine receptor, [[CXCR4]], for entry.<ref name=Coakley /><ref name=Deng>

{{cite journal | vauthors = Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di Marzio P, Marmon S, Sutton RE, Hill CM, Davis CB, Peiper SC, Schall TJ, Littman DR, Landau NR | title = Identification of a major co-receptor for primary isolates of HIV-1 | journal = Nature | volume = 381 | issue = 6584 | pages = 661–6 | year = 1996 | pmid = 8649511 | doi = 10.1038/381661a0 | bibcode = 1996Natur.381..661D | s2cid = 37973935 }}</ref><ref name=Feng>

{{cite journal | vauthors = Feng Y, Broder CC, Kennedy PE, Berger EA | title = HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor | journal = Science | volume = 272 | issue = 5263 | pages = 872–7 | year = 1996 | pmid = 8629022 | doi = 10.1126/science.272.5263.872 | bibcode = 1996Sci...272..872F | s2cid = 44455027 | pmc = 3412311 }}</ref>

Dual-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.

The ''α''-chemokine [[SDF-1 (biology)|SDF-1]], a [[Ligand (biochemistry)|ligand]] for CXCR4, suppresses replication of T-tropic HIV-1 isolates. It does this by [[Downregulation and upregulation|down-regulating]] the expression of CXCR4 on the surface of HIV target cells. M-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. However, 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<ref name="Coakley" /> and HIV can also infect a subtype of [[myeloid dendritic cells]],<ref name="Knight">{{cite journal | vauthors = Knight SC, Macatonia SE, Patterson S | title = HIV I infection of dendritic cells | journal = [[International Review of Immunology]] | volume = 6 | issue = 2–3 | pages = 163–75 | year = 1990 | pmid = 2152500 | doi = 10.3109/08830189009056627 }}</ref> which probably constitute a [[Natural reservoir|reservoir]] that maintains infection when CD4<SUP>+</SUP> T cell numbers have declined to extremely low levels.

Some people are resistant to certain strains of HIV.<ref name="Tang">{{cite journal | vauthors = Tang J, Kaslow RA | title = The impact of host genetics on HIV infection and disease progression in the era of highly active antiretroviral therapy | journal = AIDS | volume = 17 | issue = Suppl 4 | pages = S51–S60 | year = 2003 | pmid = 15080180 | doi = 10.1097/00002030-200317004-00006 | doi-access = free }}</ref> For example, people with the [[CCR5-Δ32]] 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.

[[Sexual intercourse]] is the major mode of HIV transmission. Both X4 and R5 HIV are present in the [[seminal fluid]], which enables the virus to be transmitted from a male to his [[sexual partner]]. The virions can then infect numerous cellular targets and disseminate into the whole organism. However, a selection process{{Explain|reason=explain the selection process|date=August 2018}} leads to a predominant transmission of the R5 virus through this pathway.<ref name="Zhu1993">{{cite journal | vauthors = Zhu T, Mo H, Wang N, Nam DS, Cao Y, Koup RA, Ho DD | title = Genotypic and phenotypic characterization of HIV-1 patients with primary infection | journal = Science | volume = 261 | issue = 5125 | pages = 1179–81 | year = 1993 | pmid = 8356453 | doi = 10.1126/science.8356453 | bibcode = 1993Sci...261.1179Z }}</ref><ref name="Wout">{{cite journal | vauthors = van't Wout AB, Kootstra NA, Mulder-Kampinga GA, Albrecht-van Lent N, Scherpbier HJ, Veenstra J, Boer K, Coutinho RA, Miedema F, Schuitemaker H | title = Macrophage-tropic variants initiate human immunodeficiency virus type 1 infection after sexual, parenteral, and vertical transmission | journal = Journal of Clinical Investigation | volume = 94 | issue = 5 | pages = 2060–7 | year = 1994 | pmid = 7962552 | pmc = 294642 | doi = 10.1172/JCI117560 }}</ref><ref name="Zhu1996">{{cite journal | vauthors = Zhu T, Wang N, Carr A, Nam DS, Moor-Jankowski R, Cooper DA, Ho DD | title = Genetic characterization of human immunodeficiency virus type 1 in blood and genital secretions: evidence for viral compartmentalization and selection during sexual transmission | journal = Journal of Virology | volume = 70 | issue = 5 | pages = 3098–107 | year = 1996 | pmid = 8627789 | pmc = 190172 | doi = 10.1128/JVI.70.5.3098-3107.1996 }}</ref> In 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.<ref name="Clevestig">{{cite journal | vauthors = Clevestig P, Maljkovic I, Casper C, Carlenor E, Lindgren S, Navér L, Bohlin AB, Fenyö EM, Leitner T, Ehrnst A | title = The X4 phenotype of HIV type 1 evolves from R5 in two children of mothers, carrying X4, and is not linked to transmission | journal = AIDS Research and Human Retroviruses | volume = 21 | issue = 5 | pages = 371–8 | year = 2005 | pmid = 15929699 | doi = 10.1089/aid.2005.21.371 }}</ref> These 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.<ref name="Moore">{{cite journal | vauthors = Moore JP | title = Coreceptors: implications for HIV pathogenesis and therapy | journal = Science | volume = 276 | issue = 5309 | pages = 51–2 | year = 1997 | pmid = 9122710 | doi = 10.1126/science.276.5309.51 | s2cid = 33262844 }}</ref> HIV-positive patients acquire an enormously broad spectrum of opportunistic infections, which was particularly problematic prior to the onset of [[Management of HIV/AIDS|HAART]] therapies; however, the same infections are reported among HIV-infected patients examined post-mortem following the onset of antiretroviral therapies.<ref name="pmid27611681"/> Thus, 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. A 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.<ref name="Karlsson">{{cite journal | vauthors = Karlsson A, Parsmyr K, Aperia K, Sandström E, Fenyö EM, Albert J | title = MT-2 cell tropism of human immunodeficiency virus type 1 isolates as a marker for response to treatment and development of drug resistance | journal = The Journal of Infectious Diseases | volume = 170 | issue = 6 | pages = 1367–75 | year = 1994 | pmid = 7995974 | doi = 10.1093/infdis/170.6.1367 }}</ref><ref name="Koot">{{cite journal | vauthors = Koot M, van 't Wout AB, Kootstra NA, de Goede RE, Tersmette M, Schuitemaker H | title = Relation between changes in cellular load, evolution of viral phenotype, and the clonal composition of virus populations in the course of human immunodeficiency virus type 1 infection | journal = The Journal of Infectious Diseases | volume = 173 | issue = 2 | pages = 349–54 | year = 1996 | pmid = 8568295 | doi = 10.1093/infdis/173.2.349 | doi-access = free }}</ref>

HIV-2 is much less pathogenic than HIV-1 and is restricted in its worldwide distribution to [[West Africa]]. The adoption of "accessory genes" by HIV-2 and its more [[Enzyme promiscuity|promiscuous]] pattern of co-receptor usage (including CD4-independence) may assist the virus in its adaptation to avoid innate restriction factors present in host cells. Adaptation to use normal cellular machinery to enable transmission and productive infection has also aided the establishment of HIV-2 replication in humans. A survival strategy for any infectious agent is not to kill its host, but ultimately become a [[commensal]] organism. Having achieved a low pathogenicity, over time, variants that are more successful at transmission will be selected.<ref name="CheneyandMcKnight">{{cite book |vauthors=Cheney K, McKnight A |chapter=HIV-2 Tropism and Disease | year=2010 |title=Lentiviruses and Macrophages: Molecular and Cellular Interactions | publisher=[[Caister Academic Press]] | isbn=978-1-904455-60-8 }}{{page needed|date=December 2017}}</ref>

===Replication cycle===
[[File:HIV-replication-cycle-en.svg|thumb|upright=1.8|The HIV replication cycle]]

====Entry to the cell====
[[File:HIV Membrane fusion panel.svg|thumb|upright=1.8|'''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.]]

The HIV virion enters [[macrophage]]s and CD4<SUP>+</SUP> [[T cells]] by the [[adsorption]] of [[glycoprotein]]s on its surface to receptors on the target cell followed by fusion of the [[viral envelope]] with the target cell membrane and the release of the HIV capsid into the cell.<ref name=Chan2>{{cite journal | vauthors = Chan DC, Kim PS | title = HIV entry and its inhibition | journal = Cell | volume = 93 | issue = 5 | pages = 681–4 | year = 1998 | pmid = 9630213 | doi = 10.1016/S0092-8674(00)81430-0 | s2cid = 10544941 | doi-access = free }}</ref><ref name=Wyatt>{{cite journal | vauthors = Wyatt R, Sodroski J | title = The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens | journal = Science | volume = 280 | issue = 5371 | pages = 1884–8 | year = 1998 | pmid = 9632381 | doi = 10.1126/science.280.5371.1884 | bibcode = 1998Sci...280.1884W }}</ref>

Entry to the cell begins through interaction of the trimeric envelope complex ([[gp160]] spike) on the HIV viral envelope and both [[CD4]] and a chemokine co-receptor (generally either [[CCR5]] or [[CXCR4]], but others are known to interact) on the target cell surface.<ref name=Chan2 /><ref name=Wyatt /> Gp120 binds to [[integrin]] α<sub>4</sub>β<sub>7</sub> activating [[LFA-1]], the central integrin involved in the establishment of [[virological synapse]]s, which facilitate efficient cell-to-cell spreading of HIV-1.<ref name=Arthos>{{cite journal | vauthors = Arthos J, Cicala C, Martinelli E, Macleod K, Van Ryk D, Wei D, Xiao Z, Veenstra TD, Conrad TP, Lempicki RA, McLaughlin S, Pascuccio M, Gopaul R, McNally J, Cruz CC, Censoplano N, Chung E, Reitano KN, Kottilil S, Goode DJ, Fauci AS | title = HIV-1 envelope protein binds to and signals through integrin alpha(4)beta(7), the gut mucosal homing receptor for peripheral T cells | journal = Nature Immunology | volume = 9| issue = 3 | pages = 301–9 | year = 2008 | pmid = 18264102 | doi = 10.1038/ni1566 | s2cid = 205361178 }}</ref> The gp160 spike contains binding domains for both CD4 and chemokine receptors.<ref name=Chan2 /><ref name=Wyatt />

The first step in fusion involves the high-affinity attachment of the CD4 binding domains of [[gp120]] to CD4. Once 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.<ref name=Chan2 /><ref name=Wyatt /> This allows for a more stable two-pronged attachment, which allows the [[N-terminus|N-terminal]] fusion peptide gp41 to penetrate the cell membrane.<ref name=Chan2 /><ref name=Wyatt /> [[Repeated sequence (DNA)|Repeat sequences]] in gp41, HR1, and HR2 then interact, causing the collapse of the extracellular portion of gp41 into a hairpin shape. This loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.<ref name=Chan2 /><ref name=Wyatt />

After 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.<ref name=Chan2 />{{Failed verification|date=April 2014}} During the [[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.

HIV can infect [[dendritic cell]]s (DCs) by this CD4-CCR5 route, but another route using [[Mannose receptor|mannose-specific C-type lectin receptors]] such as [[DC-SIGN]] can also be used.<ref name=Pope_2003>{{cite journal | vauthors = Pope M, Haase AT | title = Transmission, acute HIV-1 infection and the quest for strategies to prevent infection | journal = Nature Medicine | volume = 9 | issue = 7 | pages = 847–52 | year = 2003 | pmid = 12835704 | doi = 10.1038/nm0703-847 | s2cid = 26570505 | doi-access = free }}</ref> DCs are one of the first cells encountered by the virus during sexual transmission. They are currently thought to play an important role by transmitting HIV to T cells when the virus is captured in the [[mucosa]] by DCs.<ref name=Pope_2003 /> The presence of [[FEZ-1]], which occurs naturally in [[neuron]]s, is believed to prevent the infection of cells by HIV.<ref>{{cite journal | vauthors = Haedicke J, Brown C, Naghavi MH | title = The brain-specific factor FEZ1 is a determinant of neuronal susceptibility to HIV-1 infection | journal = Proceedings of the National Academy of Sciences | volume = 106 | issue = 33 | pages = 14040–14045 | date = Aug 2009 | pmid = 19667186 | pmc = 2729016 | doi = 10.1073/pnas.0900502106 | bibcode = 2009PNAS..10614040H | doi-access = free }}</ref>

[[File:Itrafig2.jpg|thumb|left|[[Clathrin-mediated endocytosis]]]]
HIV-1 entry, as well as entry of many other retroviruses, has long been believed to occur exclusively at the plasma membrane. More recently, however, productive infection by [[pH]]-independent, [[clathrin-mediated endocytosis]] of HIV-1 has also been reported and was recently suggested to constitute the only route of productive entry.<ref>{{cite journal | vauthors = Daecke J, Fackler OT, Dittmar MT, Kräusslich HG | title = Involvement of clathrin-mediated endocytosis in human immunodeficiency virus type 1 entry | journal = Journal of Virology | volume = 79 | issue = 3 | pages = 1581–1594 | date = 2005 | pmid = 15650184 | pmc = 544101 | doi = 10.1128/jvi.79.3.1581-1594.2005 }}</ref><ref>{{cite journal | vauthors = Miyauchi K, Kim Y, Latinovic O, Morozov V, Melikyan GB | title = HIV Enters Cells via Endocytosis and Dynamin-Dependent Fusion with Endosomes | journal = Cell | volume = 137 | issue = 3 | pages = 433–444 | date = 2009 | pmid = 19410541 | pmc = 2696170 | doi = 10.1016/j.cell.2009.02.046 }}</ref><ref>{{cite journal | vauthors = Koch P, Lampe M, Godinez WJ, Müller B, Rohr K, Kräusslich HG, Lehmann MJ | title = Visualizing fusion of pseudotyped HIV-1 particles in real time by live cell microscopy | journal = Retrovirology | volume = 6 | pages =  84 | date = 2009 | pmid = 19765276 | pmc = 2762461 | doi = 10.1186/1742-4690-6-84 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Thorley JA, McKeating JA, Rappoport JZ | title = Mechanisms of viral entry: sneaking in the front door | journal = Protoplasma | volume = 244 | issue = 1–4 | pages = 15–24 | date = 2010 | pmid = 20446005 | pmc = 3038234 | doi = 10.1007/s00709-010-0152-6 }}</ref><ref>{{cite journal | vauthors = Permanyer M, Ballana E, Esté JA | title = Endocytosis of HIV: anything goes | journal = Trends in Microbiology | volume = 18 | issue = 12 | pages = 543–551 | date = 2010 | pmid = 20965729 | doi = 10.1016/j.tim.2010.09.003 }}</ref>

====Replication and transcription====
[[File:Reverse Transcription.png|thumb|[[Reverse transcription]] of the HIV [[genome]] into [[double-stranded DNA]]]]

Shortly after the viral capsid enters the cell, an [[enzyme]] called [[reverse transcriptase]] liberates the positive-sense single-stranded [[RNA]] genome from the attached viral proteins and copies it into a [[cDNA|complementary DNA]] (cDNA) molecule.<ref name=Zheng>{{cite journal | vauthors = Zheng YH, Lovsin N, Peterlin BM | title = Newly identified host factors modulate HIV replication | journal = Immunology Letters | volume = 97 | issue = 2 | pages = 225–34 | year = 2005 | pmid = 15752562 | doi = 10.1016/j.imlet.2004.11.026 }}</ref> The process of reverse transcription is extremely error-prone, and the resulting mutations may cause [[Resistance to antiviral drugs|drug resistance]] or allow the virus to evade the body's immune system. The 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 (molecular biology)|sense]] DNA from the ''antisense'' cDNA.<ref>{{cite web |url=http://student.ccbcmd.edu/courses/bio141/lecguide/unit3/viruses/hivlc.html |website=Doc Kaiser's Microbiology Home Page |title=IV. Viruses> F. Animal Virus Life Cycles > 3. The Life Cycle of HIV |publisher=Community College of Baltimore County |date=January 2008 |url-status=dead |archive-url=https://web.archive.org/web/20100726222939/http://student.ccbcmd.edu/courses/bio141/lecguide/unit3/viruses/hivlc.html |archive-date=July 26, 2010 |df=mdy-all }}</ref> Together, the cDNA and its complement form a double-stranded viral DNA that is then transported into the [[cell nucleus]]. The integration of the viral DNA into the host cell's [[genome]] is carried out by another viral enzyme called [[integrase]].<ref name=Zheng />

The integrated viral DNA may then lie dormant, in the latent stage of HIV infection.<ref name=Zheng /> To actively produce the virus, certain cellular [[transcription factor]]s need to be present, the most important of which is [[NF-κB|NF-''κ''B]] (nuclear factor kappa&nbsp;B), which is upregulated when T cells become activated.<ref name=Hiscott>{{cite journal | vauthors = Hiscott J, Kwon H, Génin P | title = Hostile takeovers: viral appropriation of the NF-kB pathway | journal = Journal of Clinical Investigation | volume = 107 | issue = 2 | pages = 143–151 | year = 2001 | pmid = 11160127 | pmc = 199181 | doi = 10.1172/JCI11918 }}</ref> This means that those cells most likely to be targeted, entered and subsequently killed by HIV are those actively fighting infection.

During viral replication, the integrated DNA [[provirus]] is [[Transcription (genetics)|transcribed]] into RNA. The full-length genomic RNAs (gRNA) can be packaged into new viral particles in a [[pseudodiploid]] form. The selectivity in the packaging is explained by the structural properties of the dimeric conformer of the gRNA. The gRNA dimer is characterized  by a tandem three-way junction within the gRNA monomer, in which the SD and AUG [[Stem-loop|hairpins]], responsible for splicing and translation respectively, are sequestered and the DIS (dimerization initiation signal) hairpin is exposed. The formation of the gRNA dimer is mediated by a 'kissing'  interaction between the DIS hairpin loops of the gRNA monomers. At 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.<ref>{{Cite journal|last1=Keane|first1=Sarah C.|last2=Heng|first2=Xiao|last3=Lu|first3=Kun|last4=Kharytonchyk|first4=Siarhei|last5=Ramakrishnan|first5=Venkateswaran|last6=Carter|first6=Gregory|last7=Barton|first7=Shawn|last8=Hosic|first8=Azra|last9=Florwick|first9=Alyssa|last10=Santos|first10=Justin|last11=Bolden|first11=Nicholas C.|date=2015-05-22|title=Structure of the HIV-1 RNA packaging signal|url=http://dx.doi.org/10.1126/science.aaa9266|journal=Science|volume=348|issue=6237|pages=917–921|doi=10.1126/science.aaa9266|pmid=25999508|pmc=4492308|bibcode=2015Sci...348..917K|issn=0036-8075}}</ref> The 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.<ref>{{Cite journal|last1=Keane|first1=Sarah C.|last2=Van|first2=Verna|last3=Frank|first3=Heather M.|last4=Sciandra|first4=Carly A.|last5=McCowin|first5=Sayo|last6=Santos|first6=Justin|last7=Heng|first7=Xiao|last8=Summers|first8=Michael F.|date=2016-10-10|title=NMR detection of intermolecular interaction sites in the dimeric 5′-leader of the HIV-1 genome|journal=Proceedings of the National Academy of Sciences|volume=113|issue=46|pages=13033–13038|doi=10.1073/pnas.1614785113|pmid=27791166|pmc=5135362|bibcode=2016PNAS..11313033K |issn=0027-8424|doi-access=free}}</ref>

RNA can also be [[post-transcriptional modification|processed]] to produce mature [[messenger RNA]]s (mRNAs). In most cases, this processing involves [[RNA splicing]] to produce mRNAs that are shorter than the full-length genome. Which part of the RNA is removed during RNA splicing determines which of the HIV protein-coding sequences is translated.<ref name="Ocwieja">{{cite journal | vauthors = Ocwieja KE, Sherrill-Mix S, Mukherjee R, Custers-Allen R, David P, Brown M, Wang S, Link DR, Olson J, Travers K, Schadt E, Bushman FD | display-authors = 6 | title = Dynamic regulation of HIV-1 mRNA populations analyzed by single-molecule enrichment and long-read sequencing | journal = Nucleic Acids Research | volume = 40 | issue = 20 | pages = 10345–55 | date = November 2012 | pmid = 22923523 | pmc = 3488221 | doi = 10.1093/nar/gks753 | url = https://academic.oup.com/nar/article/40/20/10345/2414624 }}</ref>

Mature HIV mRNAs are exported from the nucleus into the [[cytoplasm]], where they are [[Translation (genetics)|translated]] to produce HIV proteins, including [[Rev (HIV)|Rev]]. As 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.<ref name=Pollard>{{cite journal | vauthors = Pollard VW, Malim MH | title = The HIV-1 Rev protein | journal = Annual Review of Microbiology | volume = 52 | pages = 491–532 | year = 1998 | pmid = 9891806 | doi = 10.1146/annurev.micro.52.1.491 }}</ref> Some of these full-length RNAs function as mRNAs that are translated to produce the structural proteins Gag and Env. Gag proteins bind to copies of the virus RNA genome to package them into new virus particles.<ref>{{cite journal | vauthors = Butsch M, Boris-Lawrie K | title = Destiny of unspliced retroviral RNA: ribosome and/or virion? | journal = Journal of Virology | volume = 76 | issue = 7 | pages = 3089–94 | date = April 2002 | pmid = 11884533 | pmc = 136024 | doi = 10.1128/JVI.76.7.3089-3094.2002 }}</ref>
HIV-1 and HIV-2 appear to package their RNA differently.<ref>{{cite journal | vauthors = Hellmund C, Lever AM | title = Coordination of Genomic RNA Packaging with Viral Assembly in HIV-1 | journal = Viruses | volume = 8 | issue = 7 | pages = 192 | date = July 2016 | pmid = 27428992 | pmc = 4974527 | doi = 10.3390/v8070192 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Soto-Rifo R, Limousin T, Rubilar PS, Ricci EP, Décimo D, Moncorgé O, Trabaud MA, André P, Cimarelli A, Ohlmann T | display-authors = 6 | title = Different effects of the TAR structure on HIV-1 and HIV-2 genomic RNA translation | journal = Nucleic Acids Research | volume = 40 | issue = 6 | pages = 2653–67 | date = March 2012 | pmid = 22121214 | pmc = 3315320 | doi = 10.1093/nar/gkr1093 }}</ref> HIV-1 will bind to any appropriate RNA.<ref>{{Cite book|url=https://books.google.com/books?id=P3vQCgAAQBAJ&q=HIV-1+will+bind+to+any+appropriate+RNA&pg=PA51|title=Role of Lipids in Virus Assembly| vauthors = Saad JS, Muriaux DM |date=2015-07-28|publisher=Frontiers Media SA|isbn=978-2-88919-582-4|language=en}}</ref> HIV-2 will preferentially bind to the mRNA that was used to create the Gag protein itself.<ref>{{cite journal | vauthors = Ricci EP, Herbreteau CH, Decimo D, Schaupp A, Datta SA, Rein A, Darlix JL, Ohlmann T | display-authors = 6 | title = In vitro expression of the HIV-2 genomic RNA is controlled by three distinct internal ribosome entry segments that are regulated by the HIV protease and the Gag polyprotein | journal = RNA | volume = 14 | issue = 7 | pages = 1443–55 | date = July 2008 | pmid = 18495939 | pmc = 2441975 | doi = 10.1261/rna.813608 }}</ref>

====Recombination====
{{Further|Genetic recombination}}
Two RNA genomes are encapsidated in each HIV-1 particle (see [[Structure and genome of HIV]]). Upon infection and replication catalyzed by reverse transcriptase, recombination between the two genomes can occur.<ref name="Hu">{{cite journal | vauthors = Hu WS, Temin HM | title = Retroviral recombination and reverse transcription | journal = Science | volume = 250 | issue = 4985 | pages = 1227–33 | year = 1990 | pmid = 1700865 | doi = 10.1126/science.1700865 | bibcode = 1990Sci...250.1227H }}</ref><ref name="Charpentier">{{cite journal | vauthors = Charpentier C, Nora T, Tenaillon O, Clavel F, Hance AJ | title = Extensive recombination among human immunodeficiency virus type 1 quasispecies makes an important contribution to viral diversity in individual patients | journal = Journal of Virology | volume = 80 | issue = 5 | pages = 2472–82 | year = 2006 | pmid = 16474154 | pmc = 1395372 | doi = 10.1128/JVI.80.5.2472-2482.2006 }}</ref> Recombination occurs as the single-strand, positive-sense RNA genomes are reverse transcribed to form DNA. During reverse transcription, the nascent DNA can switch multiple times between the two copies of the viral RNA. This form of recombination is known as copy-choice. Recombination events may occur throughout the genome. Anywhere 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.<ref name="Charpentier" />

Viral recombination produces genetic variation that likely contributes to the [[evolution]] of resistance to [[Management of HIV/AIDS|anti-retroviral therapy]].<ref>{{cite journal | vauthors = Nora T, Charpentier C, Tenaillon O, Hoede C, Clavel F, Hance AJ | title = Contribution of recombination to the evolution of human immunodeficiency viruses expressing resistance to antiretroviral treatment | journal = Journal of Virology | volume = 81 | issue = 14 | pages = 7620–8 | year = 2007 | pmid = 17494080 | pmc = 1933369 | doi = 10.1128/JVI.00083-07 }}</ref> Recombination may also contribute, in principle, to overcoming the immune defenses of the host. Yet, 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. It is unknown how often such mixed packaging occurs under natural conditions.<ref>{{cite journal | vauthors = Chen J, Powell D, Hu WS | title = High frequency of genetic recombination is a common feature of primate lentivirus replication | journal = Journal of Virology | volume = 80 | issue = 19 | pages = 9651–8 | year = 2006 | pmid = 16973569 | pmc = 1617242 | doi = 10.1128/JVI.00936-06 }}</ref>

Bonhoeffer ''et al.''<ref name=Bonhoeffer>{{cite journal | vauthors = Bonhoeffer S, Chappey C, Parkin NT, Whitcomb JM, Petropoulos CJ | title = Evidence for positive epistasis in HIV-1 | journal = Science | volume = 306 | issue = 5701 | pages = 1547–50 | year = 2004 | pmid = 15567861 | doi = 10.1126/science.1101786 | bibcode = 2004Sci...306.1547B | s2cid = 45784964 }}</ref> suggested that template switching by reverse transcriptase acts as a repair process to deal with breaks in the single-stranded RNA genome. In addition, Hu and Temin<ref name=Hu /> suggested that recombination is an adaptation for repair of damage in the RNA genomes. Strand switching (copy-choice recombination) by reverse transcriptase could generate an undamaged copy of genomic DNA from two damaged single-stranded RNA genome copies. This view of the adaptive benefit of recombination in HIV could explain why each HIV particle contains two complete genomes, rather than one. Furthermore, 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. On 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.<ref name=Bonhoeffer />

HIV-1 infection causes [[chronic inflammation]] and production of [[reactive oxygen species]].<ref>{{cite journal | vauthors = Israël N, Gougerot-Pocidalo MA | title = Oxidative stress in human immunodeficiency virus infection | journal = Cellular and Molecular Life Sciences | volume = 53 | issue = 11–12 | pages = 864–70 | year = 1997 | pmid = 9447238 | doi = 10.1007/s000180050106 | s2cid = 22663454 | pmc = 11147326 }}</ref> Thus, the HIV genome may be vulnerable to [[oxidative damage]], including breaks in the single-stranded RNA. For 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. Thus, Michod ''et al.''<ref name="pmid18295550">{{cite journal | vauthors = Michod RE, Bernstein H, Nedelcu AM | title = Adaptive value of sex in microbial pathogens | journal = Infection, Genetics and Evolution | volume = 8 | issue = 3 | pages = 267–85 | date = May 2008 | pmid = 18295550 | doi = 10.1016/j.meegid.2008.01.002 | bibcode = 2008InfGE...8..267M | url = http://www.hummingbirds.arizona.edu/Faculty/Michod/Downloads/IGE%20review%20sex.pdf | access-date = May 10, 2013 | archive-date = May 16, 2017 | archive-url = https://web.archive.org/web/20170516235741/http://www.hummingbirds.arizona.edu/Faculty/Michod/Downloads/IGE%20review%20sex.pdf | url-status = dead }}</ref> 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.

====Assembly and release====
[[File:HIV on macrophage.png|thumb|right|HIV assembling on the [[Cell membrane|surface]] of an infected [[macrophage]]. The HIV virions have been marked with a green [[fluorescent tag]] and then viewed under a fluorescent microscope.]]
The final step of the viral cycle, assembly of new HIV-1 virions, begins at the [[plasma membrane]] of the host cell. The Env polyprotein (gp160) goes through the [[endoplasmic reticulum]] and is transported to the [[Golgi apparatus]] where it is [[Bond cleavage|cleaved]] by [[furin]] resulting in the two HIV envelope glycoproteins, [[gp41]] and [[gp120]].<ref>{{cite journal | vauthors = Hallenberger S, Bosch V, Angliker H, Shaw E, Klenk HD, Garten W | title = Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160 | journal = Nature | volume = 360 | issue = 6402 | pages = 358–61 | date = November 26, 1992 | pmid = 1360148 | doi = 10.1038/360358a0 | bibcode = 1992Natur.360..358H | s2cid = 4306605 }}</ref> These are transported to the plasma membrane of the host cell where gp41 anchors gp120 to the membrane of the infected cell. The 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. The budded virion is still immature as the [[Group-specific antigen|gag]] polyproteins still need to be cleaved into the actual matrix, capsid and nucleocapsid proteins. This cleavage is mediated by the packaged viral protease and can be inhibited by antiretroviral drugs of the [[Protease inhibitor (pharmacology)|protease inhibitor]] class. The various structural components then assemble to produce a mature HIV virion.<ref name=Gelderblom>{{cite book | author= Gelderblom HR | year = 1997 | title = HIV sequence compendium | chapter = Fine structure of HIV and SIV |chapter-url=http://www.hiv.lanl.gov/content/sequence/HIV/COMPENDIUM/1997/partIII/Gelderblom.pdf | editor = Los Alamos National Laboratory | pages = 31–44 | publisher = [[Los Alamos National Laboratory]] }}</ref> Only mature virions are then able to infect another cell.

===Spread within the body===
[[File:Virus infecting lymphocytes.gif|left|thumb|Animation demonstrating cell-free spread of HIV]]
The 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".<ref name=Zhang>{{cite journal | vauthors = Zhang C, Zhou S, Groppelli E, Pellegrino P, Williams I, Borrow P, Chain BM, Jolly C | title = Hybrid Spreading Mechanisms and T Cell Activation Shape the Dynamics of HIV-1 Infection | journal = PLOS Computational Biology | volume = 11 | issue = 4 | pages = e1004179 | year = 2015 | pmid = 25837979 | pmc = 4383537 | doi = 10.1371/journal.pcbi.1004179 | arxiv = 1503.08992 | bibcode = 2015PLSCB..11E4179Z | doi-access = free }}</ref> In cell-free spread (see figure), virus particles bud from an infected T cell, enter the blood or [[extracellular fluid]] and then infect another T cell following a chance encounter.<ref name="Zhang" /> HIV 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. Firstly, an infected T cell can transmit virus directly to a target T cell via a [[Viral synapse|virological synapse]].<ref name="Arthos" /><ref name=Jolly>{{cite journal | vauthors = Jolly C, Kashefi K, Hollinshead M, Sattentau QJ | title = HIV-1 cell to cell transfer across an Env-induced, actin-dependent synapse | journal = Journal of Experimental Medicine | volume = 199 | issue = 2 | pages = 283–293 | year = 2004| pmid = 14734528 | pmc = 2211771 | doi = 10.1084/jem.20030648 }}</ref> Secondly, an [[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).<ref name=Sattentau>{{cite journal | vauthors = Sattentau Q | title = Avoiding the void: cell-to-cell spread of human viruses | journal = Nature Reviews Microbiology | volume = 6 | issue = 11 | pages = 815–826 | year = 2008| pmid = 18923409 | doi = 10.1038/nrmicro1972 | s2cid = 20991705 | doi-access = free }}</ref> Whichever pathway is used, infection by cell-to-cell transfer is reported to be much more efficient than cell-free virus spread.<ref name=Duncan>{{cite journal | vauthors = Duncan CJ, Russell RA, Sattentau QJ | title = High multiplicity HIV-1 cell-to-cell transmission from macrophages to CD4+ T cells limits antiretroviral efficacy | journal = AIDS | volume = 27 | issue = 14 | pages = 2201–2206 | year = 2013 | pmid = 24005480 | pmc = 4714465 | doi = 10.1097/QAD.0b013e3283632ec4 }}</ref> A 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]] of virions, and clustering of HIV entry receptors on the target cell towards the contact zone.<ref name="Jolly" /> Cell-to-cell spread is thought to be particularly important in [[lymphoid tissue]]s, where CD4<sup>+</sup> T cells are densely packed and likely to interact frequently.<ref name="Zhang" /> [[Intravital microscopy|Intravital imaging]] studies have supported the concept of the HIV virological synapse ''in vivo''.<ref name=Sewald>{{cite journal | vauthors = Sewald X, Gonzalez DG, Haberman AM, Mothes W | title = In vivo imaging of virological synapses | journal = Nature Communications | volume = 3 | pages =  1320 | year = 2012 | pmid = 23271654 | pmc = 3784984 | doi = 10.1038/ncomms2338 | bibcode = 2012NatCo...3.1320S }}</ref> The many dissemination mechanisms available to HIV contribute to the virus' ongoing replication in spite of anti-retroviral therapies.<ref name="Zhang" /><ref name=Sigal>{{cite journal | vauthors = Sigal A, Kim JT, Balazs AB, Dekel E, Mayo A, Milo R, Baltimore D | title = Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy | journal = Nature | volume = 477 | issue = 7362 | pages = 95–98 | year = 2011 | pmid = 21849975 | doi = 10.1038/nature10347 | bibcode = 2011Natur.477...95S | s2cid = 4409389 | url = https://resolver.caltech.edu/CaltechAUTHORS:20110922-140553274 }}</ref>

===Genetic variability===
{{Further|Subtypes of HIV}}
[[File:HIV-SIV-phylogenetic-tree straight.svg|thumb|left|The [[phylogenetic tree]] of the SIV and HIV]]
HIV differs from many viruses in that it has very high [[genetic variability]]. This diversity is a result of its fast [[#Replication cycle|replication cycle]], with the generation of about 10<sup>10</sup> virions every day, coupled with a high [[mutation rate]] of approximately 3 x 10<sup>−5</sup> per [[Nucleobase|nucleotide base]] per cycle of replication and [[Genetic recombination|recombinogenic]] properties of reverse transcriptase.<ref name=RobertsonDL>{{cite journal | vauthors = Robertson DL, Hahn BH, Sharp PM | title = Recombination in AIDS viruses | journal = Journal of Molecular Evolution | volume = 40 | issue = 3 | pages = 249–59 | year = 1995 | pmid = 7723052 | doi = 10.1007/BF00163230 | bibcode = 1995JMolE..40..249R | s2cid = 19728830 | doi-access = free }}</ref><ref name="Rambaut_2004">{{cite journal | vauthors = Rambaut A, Posada D, Crandall KA, Holmes EC | title = The causes and consequences of HIV evolution | journal = Nature Reviews Genetics | volume = 5 | issue = 52–61 | pages = 52–61 | date = January 2004 | pmid = 14708016 | doi = 10.1038/nrg1246 | s2cid = 5790569 | doi-access = free }}</ref><ref name="pmid17960579">{{cite journal | vauthors = Perelson AS, Ribeiro RM | title = Estimating drug efficacy and viral dynamic parameters: HIV and HCV | journal = Statistics in Medicine | volume = 27 | issue = 23 | pages = 4647–57 | date = October 2008 | pmid = 17960579 | doi = 10.1002/sim.3116  | s2cid = 33662579 | url = https://zenodo.org/record/1229363 }}</ref>

This complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day.<ref name=RobertsonDL /> This variability is compounded when a single cell is simultaneously infected by two or more different strains of HIV. When [[Coinfection|simultaneous infection]] occurs, the genome of progeny virions may be composed of RNA strands from two different strains. This hybrid virion then infects a new cell where it undergoes replication. As this happens, the reverse transcriptase, by jumping back and forth between the two different RNA templates, will generate a newly synthesized retroviral [[DNA sequence]] that is a recombinant between the two parental genomes.<ref name=RobertsonDL /> This recombination is most obvious when it occurs between subtypes.<ref name=RobertsonDL />

The closely related [[simian immunodeficiency virus]] (SIV) has evolved into many strains, classified by the natural host species. SIV strains of the [[Chlorocebus|African green monkey]] (SIVagm) and [[sooty mangabey]] (SIVsmm) are thought to have a long evolutionary history with their hosts. These hosts have adapted to the presence of the virus,<ref name=pmid19661993>{{cite journal | vauthors = Sodora DL, Allan JS, Apetrei C, Brenchley JM, Douek DC, Else JG, Estes JD, Hahn BH, Hirsch VM, Kaur A, Kirchhoff F, Muller-Trutwin M, Pandrea I, Schmitz JE, Silvestri G | title = Toward an AIDS vaccine: lessons from natural simian immunodeficiency virus infections of African nonhuman primate hosts | journal = Nature Medicine | volume = 15 | issue = 8 | pages = 861–865 | year = 2009 | pmid = 19661993 | pmc = 2782707 | doi = 10.1038/nm.2013 }}</ref> which is present at high levels in the host's blood, but evokes only a mild immune response,<ref>{{cite journal | vauthors = Holzammer S, Holznagel E, Kaul A, Kurth R, Norley S | title = High virus loads in naturally and experimentally SIVagm-infected African green monkeys | journal = Virology | volume = 283 | issue = 2 | pages = 324–31 | year = 2001 | pmid = 11336557 | doi = 10.1006/viro.2001.0870 | doi-access = free }}</ref> does not cause the development of simian AIDS,<ref>{{Cite journal |last1=Kurth |first1= R. |last2=Norley |first2= S. | year = 1996 | title = Why don't the natural hosts of SIV develop simian AIDS? | journal = The Journal of NIH Research | volume = 8 | pages = 33–37 }}</ref> and does not undergo the extensive mutation and recombination typical of HIV infection in humans.<ref>{{cite journal | vauthors = Baier M, Dittmar MT, Cichutek K, Kurth R | title = Development of vivo of genetic variability of simian immunodeficiency virus | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 18 | pages = 8126–30 | year = 1991 | pmid = 1896460 | pmc = 52459 | doi = 10.1073/pnas.88.18.8126 | bibcode = 1991PNAS...88.8126B | doi-access = free }}</ref>

In contrast, when these strains infect species that have not adapted to SIV ("heterologous" or similar hosts such as [[Rhesus macaque|rhesus]] or [[Crab-eating macaque|cynomologus macaques]]), the animals develop AIDS and the virus generates [[genetic diversity]] similar to what is seen in human HIV infection.<ref>{{cite journal | vauthors = Daniel MD, King NW, Letvin NL, Hunt RD, Sehgal PK, Desrosiers RC | title = A new type D retrovirus isolated from macaques with an immunodeficiency syndrome | journal = Science | volume = 223 | issue = 4636 | pages = 602–5 | year = 1984 | pmid = 6695172 | doi = 10.1126/science.6695172 | bibcode = 1984Sci...223..602D }}</ref> [[Common chimpanzee|Chimpanzee]] SIV (SIVcpz), the closest genetic relative of HIV-1, is associated with increased mortality and AIDS-like symptoms in its natural host.<ref name=pmid19626114>{{cite journal | vauthors = Keele BF, Jones JH, Terio KA, Estes JD, Rudicell RS, Wilson ML, Li Y, Learn GH, Beasley TM, Schumacher-Stankey J, Wroblewski E, Mosser A, Raphael J, Kamenya S, Lonsdorf EV, Travis DA, Mlengeya T, Kinsel MJ, Else JG, Silvestri G, Goodall J, Sharp PM, Shaw GM, Pusey AE, Hahn BH | title = Increased mortality and AIDS-like immunopathology in wild chimpanzees infected with SIVcpz | journal = Nature | volume = 460 | issue = 7254 | pages = 515–519 | year = 2009 | pmid = 19626114 | pmc = 2872475 | doi = 10.1038/nature08200 | bibcode = 2009Natur.460..515K }}</ref> SIVcpz appears to have been transmitted relatively recently to chimpanzee and human populations, so their hosts have not yet adapted to the virus.<ref name=pmid19661993 /> This virus has also lost a function of the ''[[Nef (protein)|nef]]'' gene that is present in most SIVs. For non-pathogenic SIV variants, ''nef'' suppresses T cell activation through the [[CD3 (immunology)|CD3]] marker. ''Nef''{{'s}} function in non-pathogenic forms of SIV is to [[Downregulation and upregulation|downregulate]] expression of [[Proinflammatory cytokine|inflammatory cytokines]], [[MHC class I|MHC-1]], and signals that affect T cell trafficking. In HIV-1 and SIVcpz, ''nef'' does not inhibit T-cell activation and it has lost this function. Without this function, T cell depletion is more likely, leading to immunodeficiency.<ref name=pmid19626114 /><ref>{{cite journal | vauthors = Schindler M, Münch J, Kutsch O, Li H, Santiago ML, Bibollet-Ruche F, Müller-Trutwin MC, Novembre FJ, Peeters M, Courgnaud V, Bailes E, Roques P, Sodora DL, Silvestri G, Sharp PM, Hahn BH, Kirchhoff F | title = Nef-mediated suppression of T cell activation was lost in a lentiviral lineage that gave rise to HIV-1 | journal = Cell | volume = 125 | issue = 6 | pages = 1055–67 | date = 2006 | pmid = 16777597 | doi = 10.1016/j.cell.2006.04.033 | s2cid = 15132918 | doi-access = free }}</ref>

Three groups of HIV-1 have been identified on the basis of differences in the envelope (''env'') region: M, N, and O.<ref name=Thomson>{{cite journal | vauthors = Thomson MM, Pérez-Alvarez L, Nájera R | title = Molecular epidemiology of HIV-1 genetic forms and its significance for vaccine development and therapy | journal = The Lancet Infectious Diseases | volume = 2 | issue = 8 | pages = 461–471 | year = 2002 | pmid = 12150845 | doi = 10.1016/S1473-3099(02)00343-2 }}</ref> Group M is the most prevalent and is subdivided into eight subtypes (or [[clade]]s), based on the whole genome, which are geographically distinct.<ref name=Carr>{{cite book |vauthors = Carr JK, Foley BT, Leitner T, Salminen M, Korber B, McCutchan F | year = 1998 | title = HIV sequence compendium | chapter = Reference sequences representing the principal genetic diversity of HIV-1 in the pandemic | chapter-url = http://www.hiv.lanl.gov/content/sequence/HIV/COMPENDIUM/1998/III/Carr.pdf | editor = Los Alamos National Laboratory | pages = 10–19 | publisher = [[Los Alamos National Laboratory]] | location = [[Los Alamos, New Mexico]] }}</ref> The 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]] representing the lineage of the M group of HIV-1. [[Coinfection|Co-infection]] with distinct subtypes gives rise to circulating recombinant forms (CRFs). In 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.<ref name=Osmanov>{{cite journal | vauthors = Osmanov S, Pattou C, Walker N, Schwardländer B, Esparza J | title = Estimated global distribution and regional spread of HIV-1 genetic subtypes in the year 2000 | journal =   Journal of Acquired Immune Deficiency Syndromes| volume = 29 | issue = 2 | pages = 184–190 | year = 2002 | pmid = 11832690 | doi = 10.1097/00042560-200202010-00013 | author6 = WHO-UNAIDS Network for HIV Isolation Characterization | s2cid = 12536801 }}</ref> Most HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes.<ref name=Perrin>{{cite journal | vauthors = Perrin L, Kaiser L, Yerly S | title = Travel and the spread of HIV-1 genetic variants | journal = The Lancet Infectious Diseases | volume = 3 | issue = 1 | pages = 22–27 | year = 2003 | pmid = 12505029 | doi = 10.1016/S1473-3099(03)00484-5 }}</ref> The existence of a fourth group, "P", has been hypothesised based on a virus isolated in 2009.<ref name="Plantier_2009">{{cite journal | vauthors = Plantier JC, Leoz M, Dickerson JE, De Oliveira F, Cordonnier F, Lemée V, Damond F, Robertson DL, Simon F | title = A new human immunodeficiency virus derived from gorillas | journal = Nature Medicine | volume = 15 | issue = 8 | pages = 871–2 | date = August 2009 | pmid = 19648927 | doi = 10.1038/nm.2016 | s2cid = 76837833 }}</ref><ref name="Smith 2009">{{cite web | last=Smith | first=Lewis | title=Woman found carrying new strain of HIV from gorillas | website=The Independent | date=August 3, 2009 | url=https://www.independent.co.uk/life-style/health-and-families/health-news/woman-found-carrying-new-strain-of-hiv-from-gorillas-1766627.html | access-date=November 27, 2015}}</ref> The strain is apparently derived from [[Gorilla gorilla|gorilla]] SIV (SIVgor), first isolated from [[western lowland gorilla]]s in 2006.<ref name="Plantier_2009" />

HIV-2's closest relative is SIVsm, a strain of SIV found in sooty mangabees. Since 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.<ref>{{cite journal | vauthors = Sharp PM, Hahn BH | title = The evolution of HIV-1 and the origin of AIDS | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 365 | issue = 1552 | pages = 2487–94 | date = August 2010 | pmid = 20643738 | pmc = 2935100 | doi = 10.1098/rstb.2010.0031 }}</ref><ref>{{cite journal | vauthors = Keele BF, Van Heuverswyn F, Li Y, Bailes E, Takehisa J, Santiago ML, Bibollet-Ruche F, Chen Y, Wain LV, Liegeois F, Loul S, Ngole EM, Bienvenue Y, Delaporte E, Brookfield JF, Sharp PM, Shaw GM, Peeters M, Hahn BH | display-authors = 6 | title = Chimpanzee reservoirs of pandemic and nonpandemic HIV-1 | journal = Science | volume = 313 | issue = 5786 | pages = 523–6 | date = July 2006 | pmid = 16728595 | pmc = 2442710 | doi = 10.1126/science.1126531 | bibcode = 2006Sci...313..523K }}</ref>

== Diagnosis ==
{{Main|Diagnosis of HIV/AIDS}}
[[File:Hiv-timecourse copy.svg|upright=1.35|thumb|right|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. {{legend-line|blue solid 2px|CD4<sup>+</sup> T cell count (cells per µL)}} {{legend-line|red solid 2px|HIV RNA copies per&nbsp;mL of plasma}}]]

Many HIV-positive people are unaware that they are infected with the virus.<ref name="Kumaranayake">

{{cite journal | vauthors = Kumaranayake L, Watts C | title = Resource allocation and priority setting of HIV/AIDS interventions: addressing the generalized epidemic in sub-Saharan Africa | journal = Journal of International Development | year = 2001 | pages = 451–466 | volume = 13 | issue = 4 | doi = 10.1002/jid.797}}</ref> For 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.<ref name="Kumaranayake" /> Furthermore, in 2001 only 0.5% of [[Pregnancy|pregnant women]] attending urban health facilities were counselled, tested or received their test results.<ref name="Kumaranayake" /> Again, this proportion is even lower in rural health facilities.<ref name="Kumaranayake" /> Since donors may therefore be unaware of their infection, [[Blood donation|donor blood]] and blood products used in medicine and [[medical research]] are routinely screened for HIV.<ref name="Kleinman">{{cite web | author=Kleinman S | publisher=Uptodate | date=September 2004 | url=http://www.uptodate.com/patients/content/topic.do?topicKey=blod_dis/2419 | title=Patient information: Blood donation and transfusion | archive-url=https://web.archive.org/web/20080412115832/http://www.uptodate.com/patients/content/topic.do?topicKey=blod_dis%2F2419 | archive-date=April 12, 2008 | url-status=dead | df=mdy-all }}</ref>

HIV-1 testing is initially done using an [[enzyme-linked immunosorbent assay]] (ELISA) to detect antibodies to HIV-1. Specimens 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. Specimens with a reactive ELISA result are retested in duplicate.<ref name="CDC2001">{{cite journal |author=Centers for Disease Control and Prevention | title = Revised guidelines for HIV counseling, testing, and referral | journal = MMWR Recommendations and Reports | volume = 50 | issue = RR–19 | pages = 1–57 | year = 2001 | pmid = 11718472 }}</ref> If 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]] (PCR), [[western blot]] or, less commonly, an [[immunofluorescence assay]] (IFA)). Only 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. Specimens 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.<ref name="celum">{{cite journal | vauthors = Celum CL, Coombs RW, Lafferty W, Inui TS, Louie PH, Gates CA, McCreedy BJ, Egan R, Grove T, Alexander S | title = Indeterminate human immunodeficiency virus type 1 western blots: seroconversion risk, specificity of supplemental tests, and an algorithm for evaluation | journal = The Journal of Infectious Diseases | volume = 164 | issue = 4 | pages = 656–664 | year = 1991 | pmid = 1894929 | doi = 10.1093/infdis/164.4.656 }}</ref>

{{Pie chart
 | caption= HIV deaths in 2014 excluding the U.S.:<ref>{{cite web |title=Country Comparison :: HIV/AIDS - Deaths |url=https://www.cia.gov/library/publications/the-world-factbook/rankorder/2157rank.html |publisher=The World Factbook, Central Intelligence Agency |access-date=November 22, 2015 |archive-date=April 30, 2017 |archive-url=https://web.archive.org/web/20170430003645/https://www.cia.gov/library/publications/the-world-factbook/rankorder/2157rank.html |url-status=dead }}</ref>
 | other = yes | color = cyan
 | label1 = [[Nigeria]] | value1 = 15.76
 | color1 = silver
 | label2 = [[South Africa]] | value2 = 12.51
 | color2 = #FF0000
 | label3 = [[India]] | value3 = 11.50
 | color3 = #800080
 | label4 = [[Tanzania]] | value4 = 4.169
 | color4 = #008000
 | label5 = [[Mozambique]] | value5 = 4.061
 | color5 = #00058f
 | label6 = [[Zimbabwe]] | value6 = 3.49
 | color6 = #808000
 | label7 = [[Cameroon]] | value7 = 3.09
 | color7 = #7953c1
 | label8= [[Indonesia]] | value8 = 3.04
 | color8 = #FFA500
 | label9= [[Kenya]] | value9 = 2.98
 | color9 = #704045
 | label10= [[Uganda]] | value10 = 2.97
 | color10 = #536cb6
 | label11 = [[Malawi]] | value11 = 2.94
 | color11 = #5d2e68
 | label12 = [[Democratic Republic of the Congo|DR Congo]] | value12 = 2.17
 | color12 = #add2d5
 | label13 = [[Ethiopia]] | value13 = 2.11
 | color13 = #033e88
}}

Although IFA can be used to confirm infection in these ambiguous cases, this assay is not widely used. In general, a second specimen should be collected more than a month later and retested for persons with indeterminate western blot results. Although much less commonly available, [[nucleic acid test]]ing (e.g., viral RNA or proviral DNA amplification method) can also help diagnosis in certain situations.<ref name="CDC2001" /> In addition, a few tested specimens might provide inconclusive results because of a low quantity specimen. In these situations, a second specimen is collected and tested for HIV infection.

Modern HIV testing is extremely accurate, when the [[window period]] is taken into consideration. A single screening test is correct more than 99% of the time.<ref>{{cite journal | vauthors = Chou R, Selph S, Dana T, Bougatsos C, Zakher B, Blazina I, Korthuis PT | title = Screening for HIV: systematic review to update the 2005 U.S. Preventive Services Task Force recommendation |s2cid-access=free |doi-access=free | journal = Annals of Internal Medicine | volume = 157 | issue = 10 | pages = 706–18 | date = November 2012 | pmid = 23165662 | doi = 10.7326/0003-4819-157-10-201211200-00007 | s2cid = 27494096 }}</ref> The 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.<ref name="ScreenReview2005">{{cite journal | vauthors = Chou R, Huffman LH, Fu R, Smits AK, Korthuis PT | title = Screening for HIV: a review of the evidence for the U.S. Preventive Services Task Force |s2cid-access=free |doi-access=free | journal = Annals of Internal Medicine | volume = 143 | issue = 1 | pages = 55–73 | date = July 2005 | pmid = 15998755 | doi = 10.7326/0003-4819-143-1-200507050-00010 | author6 = US Preventive Services Task Force | s2cid = 24086322 }}</ref> Testing post-exposure is recommended immediately and then at six weeks, three months, and six months.<ref name="PEP10">{{cite journal | vauthors = Tolle MA, Schwarzwald HL | title = Postexposure prophylaxis against human immunodeficiency virus |url=https://www.aafp.org/pubs/afp/issues/2010/0715/p161.html | journal = American Family Physician | volume = 82 | issue = 2 | pages = 161–6 | date = July 2010 | pmid = 20642270 |url-status=live |archive-url=https://web.archive.org/web/20231128140702/https://www.aafp.org/pubs/afp/issues/2010/0715/p161.html |archive-date= Nov 28, 2023 }}</ref>

The latest recommendations of the US [[Centers for Disease Control and Prevention (CDC)|Centers for Disease Control and Prevention]] (CDC) show that HIV testing must start with an [[immunoassay]] combination test for HIV-1 and HIV-2 [[Antibody|antibodies]] and p24 [[antigen]]. A 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. This gives rise to four possible scenarios:
* 1. HIV-1 (+) & HIV-2 (−): HIV-1 antibodies detected
* 2. HIV-1 (−) & HIV-2 (+): HIV-2 antibodies detected
* 3. HIV-1 (+) & HIV-2 (+): both HIV-1 and HIV-2 antibodies detected
* 4. HIV-1 (−) or indeterminate & HIV-2 (−): [[Nucleic acid test]] must be carried out to detect the acute infection of HIV-1 or its absence.<ref name="cdc.gov">{{cite web|title=Quick Reference Guide—Laboratory Testing for the Diagnosis of HIV Infection: Updated Recommendations|url=https://www.cdc.gov/hiv/pdf/testingHIValgorithmQuickRef.pdf|website=Centers for Disease Control and Prevention |publisher=New York State Department of Health|access-date=April 13, 2017|pages=1–2|date=June 27, 2014|archive-url=https://web.archive.org/web/20170302175531/https://www.cdc.gov/hiv/pdf/testingHIValgorithmQuickRef.pdf|archive-date=March 2, 2017|url-status=dead}}</ref>

==Research==

{{Main|HIV/AIDS research}}HIV/AIDS research includes all [[medical research]] that attempts to prevent, treat, or cure [[HIV/AIDS]], as well as fundamental research about the nature of HIV as an infectious agent and AIDS as the disease caused by HIV.

Many governments and research institutions participate in HIV/AIDS research. This research includes behavioral [[health interventions]], such as research into [[sex education]], and [[drug development]], such as research into [[microbicides for sexually transmitted diseases]], [[HIV vaccine]]s, and [[antiretroviral drug|anti-retroviral drug]]s.<ref>{{cite web |url=https://aidsinfo.nih.gov/education-materials/fact-sheets/21/58/fda-approved-hiv-medicines |title=HIV Treatment: FDA-Approved HIV Medicines |publisher=AIDSinfo |access-date=October 7, 2016 |archive-date=February 23, 2017 |archive-url=https://web.archive.org/web/20170223195011/https://aidsinfo.nih.gov/education-materials/fact-sheets/21/58/fda-approved-HIV-medicines |url-status=dead }}</ref> Other medical research areas include the topics of [[pre-exposure prophylaxis]], [[post-exposure prophylaxis]], [[circumcision and HIV|circumcision]], and [[Biological clock (aging)|accelerated aging effects]].

== Treatment and transmission==
{{Main|Management of HIV/AIDS}}{{See also|1=HIV/AIDS#Transmission|2=Undetectable = Untransmittable}}
The management of HIV/AIDS typically involves the use of multiple [[antiretroviral drugs]]. In many parts of the world, HIV has become a chronic condition, with progression to [[AIDS]] increasingly rare.

[[HIV latency]] and the resulting [[viral reservoir]] in CD4<sup>+</sup> T cells, dendritic cells, and macrophages is the main barrier to eradication of the virus.<ref name="HIV Latency" /><ref name="Rodari">{{cite journal |last1=Rodari |first1=Anthony |last2=Darcis |first2=Gilles |last3=Van Lint |first3=Carine M. |date=29 September 2021 |title=The Current Status of Latency Reversing Agents for HIV-1 Remission |journal=Annual Review of Virology |language=en |volume=8 |issue=1 |pages=491–514 |doi=10.1146/annurev-virology-091919-103029 |issn=2327-056X |pmid=34586875 |doi-access=free}}</ref>

While HIV is highly virulent, transmission through sexual contact does not occur when an HIV-positive individual maintains a consistently undetectable [[viral load]] (<50 copies/ml) due to antiretroviral treatment. This concept was first proposed by the Swiss Federal Commission for AIDS/HIV in 2008 in what is known as the [[Swiss Statement]].<ref>{{cite web |author=Swiss National AIDS Commission |date=15 October 2016 |title=The Swiss statement |url=http://i-base.info/qa/factsheets/the-swiss-statement |access-date=2 April 2019 |publisher=[[HIV i-Base]]}}</ref><ref name="Vernazza&Bernard">{{cite journal |vauthors=Vernazza P, Bernard EJ |date=29 January 2016 |title=HIV is not transmitted under fully suppressive therapy: The Swiss Statement—eight years later |journal=[[Swiss Medical Weekly]] |volume=146 |pages=w14246 |doi=10.4414/smw.2016.14246 |pmid=26824882 |doi-access=free}}</ref> Although 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."<ref>{{cite journal |author=The Lancet HIV |date=November 2017 |title=U=U taking off in 2017 |department=Editorial |journal=The Lancet. HIV |volume=4 |issue=11 |pages=e475 |doi=10.1016/S2352-3018(17)30183-2 |pmid=29096785 |doi-access=free}}</ref><ref>{{cite web |year=2019 |title=Can't Pass It On |url=https://www.tht.org.uk/our-work/our-campaigns/cant-pass-it-on |url-status=live |archive-url=https://web.archive.org/web/20190407233322/https://www.tht.org.uk/our-work/our-campaigns/cant-pass-it-on |archive-date=7 April 2019 |access-date=2 April 2019 |publisher=[[Terrence Higgins Trust]]}}</ref>

Studies that established the U=U principle include Opposites Attract,<ref name="Opposites Attract">{{cite journal | vauthors = Bavinton BR, Pinto AN, Phanuphak N, Grinsztejn B, Prestage GP, Zablotska-Manos IB, Jin F, Fairley CK, Moore R, Roth N, Bloch M, Pell C, McNulty AM, Baker D, Hoy J, Tee BK, Templeton DJ, Cooper DA, Emery S, Kelleher A, Grulich AE | display-authors = 6 | title = Viral suppression and HIV transmission in serodiscordant male couples: an international, prospective, observational, cohort study | journal = The Lancet. HIV | volume = 5 | issue = 8 | pages = e438–e447 | date = August 2018 | pmid = 30025681 | doi = 10.1016/S2352-3018(18)30132-2 | s2cid = 51702998 }}</ref> PARTNER 1,<ref name="PARTNER1">{{cite journal | vauthors = Rodger AJ, Cambiano V, Bruun T, Vernazza P, Collins S, van Lunzen J, Corbelli GM, Estrada V, Geretti AM, Beloukas A, Asboe D, Viciana P, Gutiérrez F, Clotet B, Pradier C, Gerstoft J, Weber R, Westling K, Wandeler G, Prins JM, Rieger A, Stoeckle M, Kümmerle T, Bini T, Ammassari A, Gilson R, Krznaric I, Ristola M, Zangerle R, Handberg P, Antela A, Allan S, Phillips AN, Lundgren J | display-authors = 6 | title = Sexual Activity Without Condoms and Risk of HIV Transmission in Serodifferent Couples When the HIV-Positive Partner Is Using Suppressive Antiretroviral Therapy | journal = JAMA | volume = 316 | issue = 2 | pages = 171–81 | date = July 2016 | pmid = 27404185 | doi = 10.1001/jama.2016.5148 | doi-access = free }}</ref> PARTNER 2<ref name="PARTNER2-2019" /><ref name="PARTNER2">{{cite conference|last=Rodger |first= A. (for the PARTNER study group) |title=Risk of HIV transmission through condomless sex in MSM couples with suppressive ART: The PARTNER2 Study extended results in gay men |conference=AIDS2018: 22nd International AIDS Conference |location=Amsterdam, the Netherlands |date=July 2018 |url=https://programme.aids2018.org/Abstract/Abstract/13470 |access-date=2 April 2019}}</ref> (which focused on male-male couples),<ref name="Hoffman">{{cite press release |title=The science is clear: with HIV, undetectable equals untransmittable |date=10 January 2019 |publisher=[[National Institutes of Health]] |url=https://www.nih.gov/news-events/news-releases/science-clear-hiv-undetectable-equals-untransmittable |quote=NIAID Director Anthony S. Fauci, M.D., and colleagues summarize results from large clinical trials and cohort studies validating U=U. The landmark NIH-funded HPTN 052 clinical trial showed that no linked HIV transmissions occurred among HIV serodifferent heterosexual couples when the partner living with HIV had a durably suppressed viral load. Subsequently, the PARTNER and Opposites Attract studies confirmed these findings and extended them to male-male couples. ... The success of U=U as an HIV prevention method depends on achieving and maintaining an undetectable viral load by taking ART daily as prescribed. |access-date=3 May 2019 |vauthors=Hoffman H |agency=[[National Institute of Allergy and Infectious Diseases]]}}</ref> and [[HPTN 052|HPTN052]]<ref name="HPTN052">{{cite journal | vauthors = Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, Hakim JG, Kumwenda J, Grinsztejn B, Pilotto JH, Godbole SV, Chariyalertsak S, Santos BR, Mayer KH, Hoffman IF, Eshleman SH, Piwowar-Manning E, Cottle L, Zhang XC, Makhema J, Mills LA, Panchia R, Faesen S, Eron J, Gallant J, Havlir D, Swindells S, Elharrar V, Burns D, Taha TE, Nielsen-Saines K, Celentano DD, Essex M, Hudelson SE, Redd AD, Fleming TR | display-authors = 6 | title = Antiretroviral Therapy for the Prevention of HIV-1 Transmission | journal = The New England Journal of Medicine | volume = 375 | issue = 9 | pages = 830–9 | date = September 2016 | pmid = 27424812 | pmc = 5049503 | doi = 10.1056/NEJMoa1600693 | doi-access = free | author-link1 = Myron S. Cohen }}</ref> (which focused on heterosexual couples).<ref name="Hoffman" /> These studies involved couples where one partner was HIV-positive and one was HIV-negative, and included regular HIV testing. Across 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.<ref>{{cite conference | vauthors = Hodson M |title=U=U: Talking to patients about transmission risk |conference=British HIV Association Autumn Conference 2017 |date=17 November 2017 |url=https://www.bhiva.org/file/iGHaSOpwVeAQY/MatthewHodson.pdf |access-date=3 May 2019}} ([https://www.bhiva.org/171117MatthewHodson abstract] for presentation on behalf of [[NAM Aidsmap|NAM / Aidsmap]])</ref> Following 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]], the [[British HIV Association]], and ''[[The Lancet]]'' medical journal.<ref>{{cite web |publisher=[[Prevention Access Campaign]] |title=Consensus statement: Risk of Sexual Transmission of HIV from a Person Living with HIV who has an Undetectable Viral Load |url=https://www.preventionaccess.org/consensus |date=21 July 2016 |access-date=2 April 2019}} '''Note''': When the statement and list of endorsements was retrieved, it had last been updated on 23 August 2018 and included "over 850 organizations from nearly 100 countries."</ref>

Additionally, reactivation of [[herpes simplex virus-2]] (HSV-2) in individuals with [[genital herpes]] is associated with an increase in [[CCR5|CCR-5]] enriched CD4<sup>+</sup> T cells and inflammatory dendritic cells in the dermis of ulcerated genital skin, persisting even after ulcer healing. HIV's tropism for CCR-5 positive cells contributes to the two- to threefold increased risk of HIV acquisition in persons with genital herpes. Notably, daily antiviral medication, such as [[acyclovir]], does not reduce the subclinical post-reactivation inflammation and therefore does not decrease the risk of HIV acquisition.<ref>{{cite journal | vauthors = Zhu J, Hladik F, Woodward A, Klock A, Peng T, Johnston C, Remington M, Magaret A, Koelle DM, Wald A, Corey L | display-authors = 6 | title = Persistence of HIV-1 receptor-positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisition | journal = Nature Medicine | volume = 15 | issue = 8 | pages = 886–92 | date = August 2009 | pmid = 19648930 | pmc = 2723183 | doi = 10.1038/nm.2006 }}</ref><ref>{{cite journal | vauthors = Looker KJ, Elmes JA, Gottlieb SL, Schiffer JT, Vickerman P, Turner KM, Boily MC | title = Effect of HSV-2 infection on subsequent HIV acquisition: an updated systematic review and meta-analysis | journal = The Lancet. Infectious Diseases | volume = 17 | issue = 12 | pages = 1303–1316 | date = December 2017 | pmid = 28843576 | pmc = 5700807 | doi = 10.1016/S1473-3099(17)30405-X }}</ref>

==History==
<!--This section is the same as the one at HIV/AIDS. If you change one please change the other. -->
{{Main|History of HIV/AIDS}}
{{Further|Category:HIV/AIDS by country}}

===Discovery===
{{multiple image
 | width = 160
 | image1 = Françoise Barré-Sinoussi-press conference Dec 06th, 2008-1.jpg
 | image2 = Gallo, Robert C. (3) (cropped).jpg
 | image3 = Luc Montagnier-press conference Dec 06th, 2008-6.jpg
 | footer = [[Françoise Barré-Sinoussi]], [[Robert Gallo]], and [[Luc Montagnier]], co-discoverers of HIV
}}
The first news story on "an exotic new disease" appeared May 18, 1981, in the gay newspaper ''[[New York Native]]''.<ref>{{cite news|title=On this day|work=[[News & Record]]|date=May 18, 2020|pages = 2A}}</ref>

AIDS was first clinically observed in 1981 in the United States.<ref name=M2010>{{cite book | veditors = Mandell GL, Bennett JE, Dolin R |title=Mandell, Douglas, and Bennett's principles and practice of infectious diseases |year=2010 |publisher=Churchill Livingstone/Elsevier |location=Philadelphia |isbn=978-0-443-06839-3 |chapter=Chapter 169 |edition=7th}}{{page needed|date=December 2017}}</ref> The initial cases were a cluster of injection drug users and gay men with no known cause of impaired immunity who showed symptoms of ''[[Pneumocystis jirovecii|Pneumocystis]]'' pneumonia (PCP or PJP, the latter term recognizing that the causative agent is now called ''Pneumocystis jirovecii''), a rare opportunistic infection that was known to occur in people with very compromised immune systems.<ref name=MMWR2>{{cite journal |vauthors=Gottlieb MS |title=Pneumocystis pneumonia—Los Angeles. 1981 |journal=American Journal of Public Health |volume=96 |issue=6 |pages=980–1; discussion 982–3 |year=2006 |pmid=16714472 |pmc=1470612 |doi=10.2105/AJPH.96.6.980 |url=https://www.cdc.gov/mmwr/preview/mmwrhtml/june_5.htm |archive-url=https://web.archive.org/web/20090422042240/http://www.cdc.gov/mmwr/preview/mmwrhtml/june_5.htm |url-status=live |archive-date=April 22, 2009 }}</ref> Soon thereafter, researchers at the [[NYU School of Medicine]] studied gay men developing a previously rare skin cancer called [[Kaposi's sarcoma]] (KS).<ref name="pmid7287964">{{cite journal |vauthors=Friedman-Kien AE |title=Disseminated Kaposi's sarcoma syndrome in young homosexual men |journal=Journal of the American Academy of Dermatology |volume=5 |issue=4 |pages=468–71 |date=October 1981 |pmid=7287964 |doi=10.1016/S0190-9622(81)80010-2 }}</ref><ref name="pmid6116083">{{cite journal |vauthors=Hymes KB, Cheung T, Greene JB, Prose NS, Marcus A, Ballard H, William DC, Laubenstein LJ |title=Kaposi's sarcoma in homosexual men — a report of eight cases |journal=The Lancet |volume=2 |issue=8247 |pages=598–600 |date=September 1981 |pmid=6116083 |doi=10.1016/S0140-6736(81)92740-9 |s2cid=43529542 }}</ref> Many more cases of PJP and KS emerged, alerting U.S. [[Centers for Disease Control and Prevention]] (CDC) and a CDC task force was formed to monitor the outbreak.<ref name="Basavapathruni_2007">{{cite journal |vauthors=Basavapathruni A, Anderson KS |title=Reverse transcription of the HIV-1 pandemic |journal=The FASEB Journal |volume=21 |issue=14 |pages=3795–3808 |date=December 2007 |pmid=17639073 |doi=10.1096/fj.07-8697rev |doi-access=free |s2cid=24960391 }}</ref> The earliest retrospectively described case of AIDS is believed to have been in Norway beginning in 1966.<ref>{{cite book | veditors = Lederberg J |title=Encyclopedia of Microbiology |date=2000 |publisher=Elsevier |location=Burlington |isbn=978-0-08-054848-7 |pages = 106 |edition=2nd |url=https://books.google.com/books?id=fhC_nz8eHh0C&pg=PA106 |access-date=9 June 2016}}</ref>

In 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]], the disease after which the discoverers of HIV originally named the virus.<ref name=MMWR1982a>{{cite journal |author=Centers for Disease Control |title=Persistent, generalized lymphadenopathy among homosexual males |journal=[[Morbidity and Mortality Weekly Report]] |volume=31 |issue=19 |pages=249–251 |year=1982 |pmid=6808340 |url=https://www.cdc.gov/mmwr/preview/mmwrhtml/00001096.htm }}</ref><ref name="Montagnier">{{cite journal |vauthors=Barré-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, Dauguet C, Axler-Blin C, Vézinet-Brun F, Rouzioux C, Rozenbaum W, Montagnier L |title=Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS) |journal=[[Science (journal)|Science]] |volume=220 |issue=4599 |pages=868–871 |year=1983 |pmid=6189183 |doi=10.1126/science.6189183 |bibcode=1983Sci...220..868B |s2cid=390173 }}</ref> They also used ''Kaposi's Sarcoma and Opportunistic Infections'', the name by which a task force had been set up in 1981.<ref name=MMWR1982b>{{cite journal |author=Centers for Disease Control |title=Opportunistic infections and Kaposi's sarcoma among Haitians in the United States |journal=Morbidity and Mortality Weekly Report |volume=31 |issue=26 |pages=353–354; 360–361 |year=1982 |pmid=6811853 |url=https://www.cdc.gov/mmwr/preview/mmwrhtml/00001123.htm }}</ref> In the general press, the term ''GRID'', which stood for [[gay-related immune deficiency]], had been coined.<ref name=Altman>{{Cite news |author=Altman LK |url=https://www.nytimes.com/1982/05/11/science/new-homosexual-disorder-worries-health-officials.html |title=New homosexual disorder worries health officials |work=[[The New York Times]] |date=May 11, 1982 |access-date=August 31, 2011}}</ref> The 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, [[haemophilia|hemophiliacs]], and [[Haiti]]ans.<ref>{{cite journal |title=AIDS and Syphilis: The Iconography of Disease |journal=October |volume=43 |pages=87–107 | veditors = GilmanSL |year=1987 |jstor=3397566 | vauthors = Gilman SL |doi=10.2307/3397566 }}</ref><ref name=SciRep470b>{{cite web |publisher=[[American Association for the Advancement of Science]] |date=July 28, 2006 |url=http://www.scienceonline.org/cgi/reprint/313/5786/470b.pdf |title=Making Headway Under Hellacious Circumstances |access-date=June 23, 2008 |archive-date=June 24, 2008 |archive-url=https://web.archive.org/web/20080624235131/http://www.scienceonline.org/cgi/reprint/313/5786/470b.pdf |url-status=dead }}</ref> However, after determining that AIDS was not isolated to the [[gay community]],<ref name=MMWR1982b /> it was realized that the term GRID was misleading and ''AIDS'' was introduced at a meeting in July 1982.<ref name=Kher>{{Cite magazine |author=Kher U | title=A Name for the Plague| magazine=Time | date=July 27, 1982 |url=http://www.time.com/time/80days/820727.html |access-date=March 10, 2008| archive-url=https://web.archive.org/web/20080307015307/http://www.time.com/time/80days/820727.html| archive-date=March 7, 2008 | url-status= dead}}</ref> By September 1982 the CDC started using the name AIDS.<ref name=MMWR1982c>{{cite journal |author=Centers for Disease Control |title=Update on acquired immune deficiency syndrome (AIDS)—United States |journal=Morbidity and Mortality Weekly Report |volume=31 |issue=37 |pages=507–508; 513–514 |year=1982 |pmid=6815471 }}</ref>

In 1983, two separate research groups led by American [[Robert Gallo]] and French investigators {{lang|fr|[[Françoise Barré-Sinoussi]]|italic=no}} and [[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 (journal)|Science]]''.<ref name="Gallo">{{cite journal |vauthors=Gallo RC, Sarin PS, Gelmann EP, Robert-Guroff M, Richardson E, Kalyanaraman VS, Mann D, Sidhu GD, Stahl RE, Zolla-Pazner S, Leibowitch J, Popovic M |title=Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS) |journal=[[Science (journal)|Science]] |volume=220 |issue=4599 |pages=865–867 |year=1983 |pmid=6601823 |doi=10.1126/science.6601823 |bibcode=1983Sci...220..865G }}</ref><ref name="Montagnier"/><ref>{{cite web |url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/2008/press.html |title=The 2008 Nobel Prize in Physiology or Medicine - Press Release|website=www.nobelprize.org|access-date=2018-01-28}}</ref> Gallo claimed that a virus his group had isolated from a person with AIDS was strikingly similar in [[virus structure|shape]] to other [[human T-lymphotropic virus]]es (HTLVs) his group had been the first to isolate. Gallo 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.<ref>{{cite news | vauthors = Crewdson J |title=GALLO ADMITS FRENCH DISCOVERED AIDS VIRUS |url=https://www.chicagotribune.com/news/ct-xpm-1991-05-30-9102180196-story.html |access-date=25 April 2020 |publisher=Chicago Tribune |date=30 May 1991}}</ref> Gallo's group called their newly isolated virus HTLV-III. Montagnier's group isolated a virus from a patient presenting with swelling of the [[lymph node]]s of the neck and [[asthenia|physical weakness]], two classic symptoms of primary HIV infection. Contradicting 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. Montagnier's group named their isolated virus lymphadenopathy-associated virus (LAV).<ref name="Basavapathruni_2007" /> As these two viruses turned out to be the same, in 1986 LAV and HTLV-III were renamed HIV.<ref>{{cite book | veditors = Aldrich R, Wotherspoon G |title=Who's who in gay and lesbian history |year=2001 |publisher=Routledge |location=London |isbn=978-0-415-22974-6 |pages = 154 |url=https://books.google.com/books?id=9KA7_1s6w-QC&pg=PA154 }}</ref>

Another group working contemporaneously with the Montagnier and Gallo groups was that of [[Jay A. Levy]] at the [[University of California, San Francisco]]. He independently discovered the AIDS virus in 1983 and named it the AIDS associated retrovirus (ARV).<ref>{{cite journal |author=Levy JA |display-authors=etal |year=1984 |title=Isolation of lymphocytopathic retroviruses from San Francisco patients with AIDS |journal=Science |volume=225 |issue=4664 |pages=840–842 |doi=10.1126/science.6206563 |pmid=6206563 |bibcode=1984Sci...225..840L}}</ref> This virus was very different from the virus reported by the Montagnier and Gallo groups. The 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.<ref>{{cite journal |vauthors=Levy JA, Kaminsky LS, Morrow WJ, Steimer K, Luciw P, Dina D, Hoxie J, Oshiro L |year=1985 |title=Infection by the retrovirus associated with the acquired immunodeficiency syndrome |journal=Annals of Internal Medicine |volume=103 |issue=5 |pages=694–699 |doi=10.7326/0003-4819-103-5-694 |pmid=2996401 }}</ref>

===Origins===
Both HIV-1 and HIV-2 are believed to have originated in non-human [[primate]]s in West-central Africa, and are believed to have transferred to humans (a process known as [[zoonosis]]) in the early 20th century.<ref name=Orgin2011>{{cite journal | vauthors = Sharp PM, Hahn BH | title = Origins of HIV and the AIDS Pandemic | journal = Cold Spring Harbor Perspectives in Medicine | volume = 1 | issue = 1 | pages = a006841 | year = 2011 | pmid = 22229120 | pmc = 3234451 | doi = 10.1101/cshperspect.a006841 }}</ref><ref name=Faria2014>{{cite journal | vauthors = Faria NR, Rambaut A, Suchard MA, Baele G, Bedford T, Ward MJ, Tatem AJ, Sousa JD, Arinaminpathy N, Pépin J, Posada D, Peeters M, Pybus OG, Lemey P | title = The early spread and epidemic ignition of HIV-1 in human populations | journal = Science | volume = 346 | issue = 6205 | pages = 56–61 | year = 2014 | pmid = 25278604| pmc = 4254776| doi = 10.1126/science.1256739 | bibcode = 2014Sci...346...56F }}</ref>

HIV-1 appears to have originated in southern [[Cameroon]] through the evolution of SIVcpz, a [[simian immunodeficiency virus]] (SIV) that infects wild [[common chimpanzee|chimpanzee]]s (HIV-1 descends from the SIVcpz endemic in the chimpanzee subspecies ''[[Central chimpanzee|Pan troglodytes troglodytes]]'').<ref name="pmid9989410">{{cite journal | vauthors = Gao F, Bailes E, Robertson DL, Chen Y, Rodenburg CM, Michael SF, Cummins LB, Arthur LO, Peeters M, Shaw GM, Sharp PM, Hahn BH | title = Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes | journal = Nature | volume = 397 | issue = 6718 | pages = 436–41 | year = 1999 | pmid = 9989410 | doi = 10.1038/17130 | bibcode = 1999Natur.397..436G | s2cid = 4432185 | doi-access = free }}</ref><ref name=Keele>{{cite journal | vauthors = Keele BF, Van Heuverswyn F, Li Y, Bailes E, Takehisa J, Santiago ML, Bibollet-Ruche F, Chen Y, Wain LV, Liegeois F, Loul S, Ngole EM, Bienvenue Y, Delaporte E, Brookfield JF, Sharp PM, Shaw GM, Peeters M, Hahn BH | title = Chimpanzee reservoirs of pandemic and nonpandemic HIV-1 | journal = Science | volume = 313 | issue = 5786 | pages = 523–6 | year = 2006 | pmid = 16728595 | pmc = 2442710 | doi = 10.1126/science.1126531 | bibcode = 2006Sci...313..523K }}</ref> The closest relative of HIV-2 is SIVsmm, a virus of the [[sooty mangabey]] (''Cercocebus atys atys''), an [[Old World monkey]] living in littoral West Africa (from southern [[Senegal]] to western [[Ivory Coast|Côte d'Ivoire]]).<ref name=Reeves /> [[New World monkey]]s such as the [[Night monkey|owl monkey]] are resistant to HIV-1 infection, possibly because of a [[fusion gene|genomic fusion]] of two viral resistance genes.<ref name=Goodier>{{cite journal | vauthors = Goodier JL, Kazazian HH | title = Retrotransposons revisited: the restraint and rehabilitation of parasites | journal = Cell | volume = 135 | issue = 1 | pages = 23–35 | year = 2008 | pmid = 18854152 | doi = 10.1016/j.cell.2008.09.022 | s2cid = 3093360 | doi-access = free }}</ref>

HIV-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.<ref name="Sharp2001">{{cite journal | vauthors = Sharp PM, Bailes E, Chaudhuri RR, Rodenburg CM, Santiago MO, Hahn BH | title = The origins of acquired immune deficiency syndrome viruses: where and when? | journal = Philosophical Transactions of the Royal Society B | volume = 356 | issue = 1410 | pages = 867–76 | year = 2001 | pmid = 11405934 | pmc = 1088480 | doi = 10.1098/rstb.2001.0863 }}</ref>

[[File:SIV primates.jpg|left|upright=1.8|thumb|Left to right: the [[African green monkey]] source of [[Simian immunodeficiency virus|SIV]], the [[sooty mangabey]] source of [[HIV-2]], and the chimpanzee source of [[HIV-1]]]]
There is evidence that humans who participate in [[bushmeat]] activities, either as hunters or as bushmeat vendors, commonly acquire SIV.<ref name=Kalish2005>{{cite journal | vauthors = Kalish ML, Wolfe ND, Ndongmo CB, McNicholl J, Robbins KE, Aidoo M, Fonjungo PN, Alemnji G, Zeh C, Djoko CF, Mpoudi-Ngole E, Burke DS, Folks TM | title = Central African hunters exposed to simian immunodeficiency virus | journal = Emerging Infectious Diseases | volume = 11 | issue = 12 | pages = 1928–30 | year = 2005 | pmid = 16485481 | pmc = 3367631 | doi = 10.3201/eid1112.050394 }}</ref> However, SIV is a weak virus, and it is typically suppressed by the human immune system within weeks of infection. It 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.<ref name=Marx2001>{{cite journal | vauthors = Marx PA, Alcabes PG, Drucker E | title = Serial human passage of simian immunodeficiency virus by unsterile injections and the emergence of epidemic human immunodeficiency virus in Africa | journal = Philosophical Transactions of the Royal Society B | volume = 356 | issue = 1410 | pages = 911–20 | year = 2001 | pmid = 11405938 | pmc = 1088484 | doi = 10.1098/rstb.2001.0867 }}</ref> Furthermore, 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.

Specific 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. Genetic studies of the virus suggest that the most recent common ancestor of the HIV-1 M group dates back to {{Circa|1910}}.<ref name=Worobey2008>{{cite journal | vauthors = Worobey M, Gemmel M, Teuwen DE, Haselkorn T, Kunstman K, Bunce M, Muyembe JJ, Kabongo JM, Kalengayi RM, Van Marck E, Gilbert MT, Wolinsky SM | title = Direct evidence of extensive diversity of HIV-1 in Kinshasa by 1960 | journal = Nature | volume = 455 | issue = 7213 | pages = 661–4 | year = 2008 | pmid = 18833279 | pmc = 3682493 | doi = 10.1038/nature07390 | bibcode = 2008Natur.455..661W }}</ref> Proponents of this dating link the HIV epidemic with the emergence of [[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]], and the concomitant high frequency of [[genital ulcer]] diseases (such as [[syphilis]]) in nascent colonial cities.<ref name=Sousa2010>{{cite journal | vauthors = de Sousa JD, Müller V, Lemey P, Vandamme AM | title = High GUD incidence in the early 20th century created a particularly permissive time window for the origin and initial spread of epidemic HIV strains | journal = PLOS ONE | volume = 5 | issue = 4 | pages = e9936 | year = 2010 | pmid = 20376191 | pmc = 2848574 | doi = 10.1371/journal.pone.0009936 | veditors = Martin DP | bibcode = 2010PLoSO...5.9936S | doi-access = free }}</ref> While transmission rates of HIV during vaginal intercourse are typically low, they are increased manyfold if one of the partners has a [[Sexually transmitted disease|sexually transmitted infection]] resulting in genital ulcers. Early 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 [[Kinshasa|Leopoldville (currently 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]].<ref name=Sousa2010 />

The earliest, well-documented case of HIV in a human dates back to 1959 in the [[Belgian Congo]].<ref name=Zhu>{{cite journal | vauthors = Zhu T, Korber BT, Nahmias AJ, Hooper E, Sharp PM, Ho DD | title = An African HIV-1 Sequence from 1959 and Implications for the Origin of the epidemic | journal = Nature | volume = 391 | issue = 6667 | pages = 594–7 | year = 1998 | pmid = 9468138 | doi = 10.1038/35400 | bibcode = 1998Natur.391..594Z | s2cid = 4416837 | doi-access = free }}</ref> The 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]] presented with symptoms in 1966 and died in 1969.<ref>{{cite news| vauthors = Kolata G |title=Boy's 1969 death suggests AIDS invaded U.S. several times|work=[[The New York Times]] |date=October 28, 1987 |url=https://query.nytimes.com/gst/fullpage.html?res=9B0DEFD6173AF93BA15753C1A961948260 |access-date=February 11, 2009}}</ref>

An 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.<ref name=Marx2001 /><ref name="Chitnis2000">{{cite journal | vauthors = Chitnis A, Rawls D, Moore J | title = Origin of HIV type 1 in colonial French Equatorial Africa? | journal = AIDS Research and Human Retroviruses | volume = 16 | issue = 1 | pages = 5–8 | date = January 2000 | pmid = 10628811 | doi = 10.1089/088922200309548 | s2cid = 17783758 }}</ref><ref name="McNeil">{{cite news|first=Donald Jr. |last=McNeil|author-link=Donald McNeil, Jr|date=September 16, 2010|title=Precursor to H.I.V. was in monkeys for millennia|work=[[The New York Times]]|url=https://www.nytimes.com/2010/09/17/health/17aids.html |archive-url=https://ghostarchive.org/archive/20220103/https://www.nytimes.com/2010/09/17/health/17aids.html |archive-date=2022-01-03 |url-access=subscription |url-status=live|access-date=September 17, 2010|quote=Dr. Marx believes that the crucial event was the introduction into Africa of millions of inexpensive, mass-produced syringes in the 1950s. ... suspect that the growth of colonial cities is to blame. Before 1910, no Central African town had more than 10,000 people. But urban migration rose, increasing sexual contacts and leading to red-light districts.}}{{cbignore}}</ref> Research 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.<ref name=":0">{{cite journal | vauthors = Wertheim JO, Worobey M | title = Dating the age of the SIV lineages that gave rise to HIV-1 and HIV-2 | journal = PLOS Computational Biology | volume = 5 | issue = 5 | pages = e1000377 | date = May 2009 | pmid = 19412344 | pmc = 2669881 | doi = 10.1371/journal.pcbi.1000377 | bibcode = 2009PLSCB...5E0377W | doi-access = free }}</ref> The dispersed timing of these transmissions to humans implies that no single external factor is needed to explain the cross-species transmission of HIV. This 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.<ref name=":0" />

== See also ==
{{Portal|Medicine|Viruses}}
* [[Antiviral drug]]
* [[Discovery and development of HIV-protease inhibitors]]
* [[HIV/AIDS denialism]]
* [[HIVToolbox]]
* [[World AIDS Day]]

== References ==
{{Reflist|32em}}

== Further reading ==
{{Refbegin}}
* {{cite journal | vauthors = Berlier W, Bourlet T, Lawrence P, Hamzeh H, Lambert C, Genin C, Verrier B, Dieu-Nosjean MC, Pozzetto B, Delézay O | title = Selective sequestration of X4 isolates by human genital epithelial cells: Implication for virus tropism selection process during sexual transmission of HIV | journal = Journal of Medical Virology | volume = 77 | issue = 4 | pages = 465–74 | year = 2005 | pmid = 16254974 | doi = 10.1002/jmv.20478 | s2cid = 25762969 }}
* {{cite book|author=[[Joint United Nations Programme on HIV/AIDS]] (UNAIDS) |title=Global HIV/AIDS Response, Epidemic update and health sector progress towards universal access|year=2011|publisher=Joint United Nations Programme on HIV/AIDS|url=http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2011/20111130_UA_Report_en.pdf}}
* {{cite journal | vauthors = Muciaccia B, Padula F, Vicini E, Gandini L, Lenzi A, Stefanini M | title = Beta-chemokine receptors 5 and 3 are expressed on the head region of human spermatozoon | journal = The FASEB Journal | volume = 19 | issue = 14 | pages = 2048–50 | year = 2005 | pmid = 16174786 | doi = 10.1096/fj.05-3962fje | doi-access = free | hdl = 11573/361629 | s2cid = 7928126 }}
{{Refend}}

== External links ==
{{Sister project links|b=Sexual Health/Sexually Transmitted Diseases#HIV|commons=Category:HIV|n=Category:AID|s=no|q=no|v=no}}
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