Editing HIV (section)

===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>