Editing HIV (section)

==Virology==
{| class="wikitable" style="float:center; font-size:85%; margin-left:15px;"
|+Comparison of HIV species
|-
! Species !! [[Virulence]] !! [[Infectivity]] !! Prevalence !! Inferred origin
|-
! HIV-1 (''Lentivirus humimdef1'')
| High || High || Global || [[Common chimpanzee]]
|-
! HIV-2 (''Lentivirus humimdef2'')
| 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>

Both HIV-1 and HIV-2 have gained an additional classification according to the [[International Committee on Taxonomy of Viruses]], with the change being approved in 2020, to belong to the species called "''Lentivirus humimdef1''" and "''Lentivirus humimdef2''" for HIV-1 and HIV-2 respectively.<ref>{{Cite web |title=Genus: Lentivirus {{!}} ICTV |url=https://ictv.global/report/chapter/retroviridae/retroviridae/lentivirus |access-date=2025-01-15 |website=ictv.global}}</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 | url-access = subscription }}</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 leads to a predominant transmission of the R5 virus through this pathway, hypothesized to be because some variants may more easily infect cells when entering the body, or because some variants replicate more efficiently after initial infection and become the dominant variant in blood.<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===
{{update|section|date=February 2025}}
[[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>