Editing HIV (section)

===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>