View source for CCR5-Δ32

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'''CCR5-Δ32''' (or CCR5-D32 or CCR5 delta 32) is a genetic variant of the [[CCR5]] gene characterized by a 32-base-pair deletion that produces a nonfunctional receptor on the surface of immune cells, conferring strong resistance to HIV-1 infection in individuals who inherit two copies of the mutation (homozygotes).<ref name="Jasinska_2022">{{cite journal | vauthors = Jasinska AJ, Pandrea I, Apetrei C | title = CCR5 as a Coreceptor for Human Immunodeficiency Virus and Simian Immunodeficiency Viruses: A Prototypic Love-Hate Affair | journal = Frontiers in Immunology | volume = 13 | pages = 835994 | date = 2022 | pmid = 35154162 | pmc = 8829453 | doi = 10.3389/fimmu.2022.835994 | doi-access = free }}</ref><ref name="Galvani_2003">{{cite journal | vauthors = Galvani AP, Slatkin M | title = Evaluating plague and smallpox as historical selective pressures for the CCR5-Delta 32 HIV-resistance allele | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 25 | pages = 15276–15279 | date = December 2003 | pmid = 14645720 | pmc = 299980 | doi = 10.1073/pnas.2435085100 | doi-access = free | bibcode = 2003PNAS..10015276G }}</ref><ref name="Stephens_1998">{{cite journal | vauthors = Stephens JC, Reich DE, Goldstein DB, Shin HD, Smith MW, Carrington M, Winkler C, Huttley GA, Allikmets R, Schriml L, Gerrard B, Malasky M, Ramos MD, Morlot S, Tzetis M, Oddoux C, di Giovine FS, Nasioulas G, Chandler D, Aseev M, Hanson M, Kalaydjieva L, Glavac D, Gasparini P, Kanavakis E, Claustres M, Kambouris M, Ostrer H, Duff G, Baranov V, Sibul H, Metspalu A, Goldman D, Martin N, Duffy D, Schmidtke J, Estivill X, O'Brien SJ, Dean M | title = Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes | journal = American Journal of Human Genetics | volume = 62 | issue = 6 | pages = 1507–1515 | date = June 1998 | pmid = 9585595 | pmc = 1377146 | doi = 10.1086/301867 }}</ref>

CCR5 Δ32 is a 32-base-pair deletion that introduces a premature [[stop codon]] into the CCR5 receptor locus, resulting in a nonfunctional receptor.<ref name="Dean_1996">{{cite journal | vauthors = Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, Goedert JJ, Buchbinder SP, Vittinghoff E, Gomperts E, Donfield S, Vlahov D, Kaslow R, Saah A, Rinaldo C, Detels R, O'Brien SJ | title = Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study | journal = Science | location = New York, N.Y. | volume = 273 | issue = 5283 | pages = 1856–1862 | date = September 1996 | pmid = 8791590 | doi = 10.1126/science.273.5283.1856 | s2cid = 21160580 | bibcode = 1996Sci...273.1856D | url = https://zenodo.org/record/1231080 }}</ref><ref name="Samson et al. 1996">{{cite journal | vauthors = Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM, Saragosti S, Lapoumeroulie C, Cognaux J, Forceille C, Muyldermans G, Verhofstede C, Burtonboy G, Georges M, Imai T, Rana S, Yi Y, Smyth RJ, Collman RG, Doms RW, Vassart G, Parmentier M | title = Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene | journal = Nature | volume = 382 | issue = 6593 | pages = 722–725 | date = August 1996 | pmid = 8751444 | doi = 10.1038/382722a0 | s2cid = 4370818 | bibcode = 1996Natur.382..722S }}</ref> CCR5 is required for M-tropic HIV-1 virus entry.<ref name="Liu_1996">{{cite journal | vauthors = Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, Horuk R, MacDonald ME, Stuhlmann H, Koup RA, Landau NR | title = Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection | journal = Cell | volume = 86 | issue = 3 | pages = 367–377 | date = August 1996 | pmid = 8756719 | doi = 10.1016/s0092-8674(00)80110-5 | s2cid = 16965624 | doi-access = free }}</ref> Individuals [[homozygous]] (denoted Δ32/Δ32) for CCR5 Δ32 do not express functional CCR5 receptors on their cell surfaces and are resistant to [[HIV-1]] infection, despite multiple high-risk exposures.<ref name="Liu_1996" /> Individuals [[heterozygous]] (+/Δ32) for the mutant [[allele]] have a greater than 50% reduction in functional CCR5 receptors on their cell surfaces due to dimerization between mutant and wild-type receptors that interferes with transport of CCR5 to the cell surface.<ref name="Benkirane_1997">{{cite journal | vauthors = Benkirane M, Jin DY, Chun RF, Koup RA, Jeang KT | title = Mechanism of transdominant inhibition of CCR5-mediated HIV-1 infection by ccr5delta32 | journal = The Journal of Biological Chemistry | volume = 272 | issue = 49 | pages = 30603–30606 | date = December 1997 | pmid = 9388191 | doi = 10.1074/jbc.272.49.30603 | doi-access = free }}</ref> Heterozygote carriers are resistant to HIV-1 infection relative to wild types and when infected, heterozygotes exhibit reduced [[viral load]]s and a 2-3-year-slower progression to AIDS relative to wild types.<ref name="Dean_1996" /><ref name="Liu_1996" /><ref name="Michael_1997">{{cite journal | vauthors = Michael NL, Louie LG, Rohrbaugh AL, Schultz KA, Dayhoff DE, Wang CE, Sheppard HW | title = The role of CCR5 and CCR2 polymorphisms in HIV-1 transmission and disease progression | journal = Nature Medicine | volume = 3 | issue = 10 | pages = 1160–1162 | date = October 1997 | pmid = 9334732 | doi = 10.1038/nm1097-1160 | s2cid = 23196048 }}</ref> Heterozygosity for this mutant allele also has shown to improve one's virological response to anti-retroviral treatment.<ref>{{cite journal | vauthors = Laurichesse JJ, Persoz A, Theodorou I, Rouzioux C, Delfraissy JF, Meyer L | title = Improved virological response to highly active antiretroviral therapy in HIV-1-infected patients carrying the CCR5 Delta32 deletion | journal = HIV Medicine | volume = 8 | issue = 4 | pages = 213–219 | date = May 2007 | pmid = 17461848 | doi = 10.1111/j.1468-1293.2007.00455.x | s2cid = 24900064 | doi-access = free }}</ref> CCR5 Δ32 has a heterozygote frequency of 9% in Europe, and a homozygote frequency of 1%.<ref>{{cite book | vauthors = Murphy K, Weaver C | title = Janeway's Immunobiology 9th Edition | pages = 582 | date = 2016 | publisher = Garland Science | isbn = 978-0-8153-4550-3 }}</ref>

Recent research indicates that CCR5 Δ32 enhances cognition and memory. In 2016, researchers showed that removing the CCR5 gene from mice significantly improved their memory.<ref name="techreview-ccr5">{{cite web | title = China's CRISPR twins might have had their brains inadvertently enhanced | url = https://www.technologyreview.com/s/612997/the-crispr-twins-had-their-brains-altered/ | website = Technology Review | access-date = 22 February 2019 }}</ref>  CCR5 is a powerful suppressor for neuronal plasticity, learning, and memory; CCR5 over-activation by viral proteins may contribute to HIV-associated cognitive deficits.<ref name="Zhou_2016">{{cite journal | vauthors = Zhou M, Greenhill S, Huang S, Silva TK, Sano Y, Wu S, Cai Y, Nagaoka Y, Sehgal M, Cai DJ, Lee YS, Fox K, Silva AJ | title = CCR5 is a suppressor for cortical plasticity and hippocampal learning and memory | journal = eLife | volume = 5 | date = December 2016 | pmid = 27996938 | pmc = 5213777 | doi = 10.7554/eLife.20985 | doi-access = free }}</ref>

== HIV ==
[[Human Immunodeficiency Virus|Human Immunodeficiency virus]] uses CCR5 receptor to target and infect host [[T cell|T-cells]] in humans. It weakens the immune system by destroying the CD4+ T-helper cells, making the body more susceptible to other infections. CCR5-Δ32 is an allelic variant of CCR5 gene with a 32 base pair deletion that results in a truncated receptor. People with this allele are resistant to AIDS as HIV cannot bind to the non-functional CCR5 receptor. An unusually high frequency of this allele is found in European [[Caucasian race|Caucasian]] population, with an observed cline towards the north.<ref name="Galvani_2003a" /> Most researchers have attributed the current frequency of this allele to two major epidemics of human history: [[Plague (disease)|plague]] and [[smallpox]]. Although this allele originated much earlier, its frequency rose dramatically about 700 years ago.<ref name="Galvani_2003a" /> This led scientists to believe that bubonic plague acted as a selective pressure that drove CCR5-Δ32 to high frequency. It was speculated that allele may have provided protection against the ''[[Yersinia pestis]]'', which is the causative agent for plague. Many [[in vivo]] mouse studies have refuted this claim by showing no protective effects of  CCR5-Δ32 allele in mice infected with ''Y. pestis''.<ref>{{Cite journal | vauthors = Mecsas J, Franklin G, Kuziel WA, Brubaker RR, Falkow S, Mosier DE | title = Evolutionary genetics: CCR5 mutation and plague protection | journal = Nature | volume = 427 | issue = 6975 | pages = 606 | date = 2004-02-12 | pmid = 14961112 | doi = 10.1038/427606a | issn = 1476-4687 | bibcode = 2004Natur.427..606M | s2cid = 4430235 | doi-access = free }}</ref><ref>{{Cite journal | vauthors = Styer KL, Click EM, Hopkins GW, Frothingham R, Aballay A | title = Study of the role of CCR5 in a mouse model of intranasal challenge with Yersinia pestis | journal = Microbes and Infection | volume = 9 | issue = 9 | pages = 1135–1138 | date = 2007-07-01 | pmid = 17644454 | pmc = 2754264 | doi = 10.1016/j.micinf.2007.04.012 | issn = 1286-4579 }}</ref> Another theory that has gained more scientific support links the current frequency of the allele to smallpox epidemic. Although plague has killed a greater number people in a given time period, smallpox has collectively taken more lives.<ref name="Galvani_2003a" /> As [[smallpox]] has been dated back to 2000 years, a longer time period would have given smallpox enough time to exert selective pressure given an earlier origin of CCR5-Δ32.<ref name="Galvani_2003a" /> Population genetic models that analyzed geographic and temporal distribution of both plague and smallpox provide a much stronger evidence for smallpox as the driving factor of CCR5-Δ32.<ref name="Galvani_2003a">{{Cite journal | vauthors = Galvani AP, Slatkin M | title = Evaluating plague and smallpox as historical selective pressures for the CCR5-Delta 32 HIV-resistance allele | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 25 | pages = 15276–15279 | date = 2003-12-09 | pmid = 14645720 | pmc = 299980 | doi = 10.1073/pnas.2435085100 | issn = 0027-8424 | bibcode = 2003PNAS..10015276G | doi-access = free }}</ref> Smallpox has a higher mortality rate than plague, and it mostly affects children under the age of ten.<ref name="Galvani_2003a" /> From an evolutionary viewpoint, this results in greater loss of reproductive potential from a population which may explain increased selective pressure by smallpox. Smallpox was more prevalent in regions where higher CCR5-Δ32 frequencies are seen. [[Myxoma virus|Myxoma]] and [[Variola Major|variola major]] belong to the same family of viruses and myxoma has been shown to use [[CCR5]] receptor to enter its host.<ref>{{Cite journal | vauthors = Lalani AS, Masters J, Zeng W, Barrett J, Pannu R, Everett H, Arendt CW, McFadden G | title = Use of chemokine receptors by poxviruses | journal = Science | location = New York, N.Y. | volume = 286 | issue = 5446 | pages = 1968–1971 | date = 1999-12-03 | pmid = 10583963 | doi = 10.1126/science.286.5446.1968 | issn = 0036-8075 }}</ref> Moreover, ''Yersinia'' is a bacterium which is biologically distinct from viruses and is unlikely to have similar mechanism of transmission. Recent evidence provides a strong support for smallpox as the selective agent for CCR5-Δ32.

== Haplotype and architecture ==

Genetic studies published in 2025<ref name="Ravn_2025">{{cite journal | vauthors = Ravn K, Cobuccio L, Muktupavela RA, Meisner J, Danielsen LS, Benros ME, Korneliussen TS, Sikora M, Willerslev E, Allentoft ME, Irving-Pease EK, Rasmussen S | title = Tracing the evolutionary history of the CCR5delta32 deletion via ancient and modern genomes | journal = Cell | date = May 2025 | pmid = 40328257 | doi = 10.1016/j.cell.2025.04.015 | doi-access = free }}</ref> revealed that the CCR5Δ32 deletion is part of a specific haplotype, termed Haplotype A, which includes 86 linked variants in high linkage disequilibrium (LD). Within this haplotype, two single nucleotide polymorphisms (SNPs), rs113341849 and rs113010081, are in perfect LD (r² = 1) with CCR5Δ32 and thus statistically indistinguishable in genotype data. This haplotype is located on chromosome 3 (3p21.31), spans approximately 0.19 megabases, and encompasses several chemokine receptor genes, including ''[[CCR3 (gene)|CCR3]]'', ''[[CCR2]]'', ''[[CCR5]]'', and ''[[CCRL2]]''. Although two additional haplotypes, B and C, were identified in the region, only Haplotype A carries the CCR5Δ32 deletion. The configuration of the three haplotypes—A, B, and C—was illustrated in Figure 1A of the study.<ref name="Ravn_2025" />

== Evolutionary history ==

The CCR5 Δ32 allele is notable for its recent origin, unexpectedly high frequency, and distinct geographic distribution,<ref name="Galvani_2005">{{cite journal | vauthors = Galvani AP, Novembre J | title = The evolutionary history of the CCR5-Delta32 HIV-resistance mutation | journal = Microbes and Infection | volume = 7 | issue = 2 | pages = 302–309 | date = February 2005 | pmid = 15715976 | doi = 10.1016/j.micinf.2004.12.006 | doi-access = free }}</ref> which together suggest that (a) it arose from a single mutation, and (b) it was historically subject to positive selection.

Two studies have used linkage analysis to estimate the age of the CCR5 Δ32 deletion, assuming that the amount of recombination and mutation observed on genomic regions surrounding the CCR5 Δ32 deletion would be proportional to the age of the deletion.<ref name="Stephens_1998" /><ref name="Libert_1998" /> Using a sample of 4000 individuals from 38 ethnic populations, Stephens et al. estimated that the CCR5-Δ32 deletion occurred 700 years ago (275–1875, 95% confidence interval). Another group, Libert et al. (1998), used microsatellite mutations to estimate the age of the CCR5 Δ32 mutation to be 2100 years (700–4800, 95% confidence interval).  On the basis of observed recombination events, they estimated the age of the mutation to be 2250 years (900–4700, 95% confidence interval).<ref name="Libert_1998" /> A third hypothesis relies on the north-to-south gradient of allele frequency in Europe, which shows that the highest allele frequency occurred in the [[Nordic countries]] and lowest allele frequency in southern Europe.  Because the Vikings historically occupied these countries, it may be possible that the allele spread throughout Europe due to the Viking dispersal in the 8th to 10th centuries.<ref name="Lucotte_2001">{{cite journal | vauthors = Lucotte G | title = Distribution of the CCR5 gene 32-basepair deletion in West Europe. A hypothesis about the possible dispersion of the mutation by the Vikings in historical times | journal = Human Immunology | volume = 62 | issue = 9 | pages = 933–936 | date = September 2001 | pmid = 11543895 | doi = 10.1016/S0198-8859(01)00292-0 }}</ref> Vikings were later replaced by the [[Varangians]] in Russia, which may have contributed to the observed east-to-west cline of allele frequency.<ref name="Galvani_2005" /><ref name="Lucotte_2001" />

HIV-1 was initially transmitted from chimpanzees (''Pan troglodytes'') to humans in the early 1900s in Southeast Cameroon, Africa,<ref name="Keele_2006">{{cite journal | vauthors = Keele BF, Van Heuverswyn F, Li Y, Bailes E, Takehisa J, Santiago ML, Bibollet-Ruche F, Chen Y, Wain LV, Liegeois F, Loul S, Ngole EM, Bienvenue Y, Delaporte E, Brookfield JF, Sharp PM, Shaw GM, Peeters M, Hahn BH | title = Chimpanzee reservoirs of pandemic and nonpandemic HIV-1 | journal = Science | location = New York, N.Y. | volume = 313 | issue = 5786 | pages = 523–526 | date = July 2006 | pmid = 16728595 | pmc = 2442710 | doi = 10.1126/science.1126531 | bibcode = 2006Sci...313..523K }}</ref> through exposure to infected blood and body fluids while butchering bushmeat.<ref name="Hahn_2000">{{cite journal | vauthors = Hahn BH, Shaw GM, De Cock KM, Sharp PM | title = AIDS as a zoonosis: scientific and public health implications | journal = Science | location = New York, N.Y. | volume = 287 | issue = 5453 | pages = 607–614 | date = January 2000 | pmid = 10649986 | doi = 10.1126/science.287.5453.607 | bibcode = 2000Sci...287..607H }}</ref> However, HIV-1 was effectively absent from Europe until the 1980s.<ref>{{cite web | vauthors = Matic S | title = HIV/AIDS in Europe: Moving from death sentence to chronic disease management | url = https://www.who.int/hiv/pub/idu/hiv_europe.pdf | publisher = World Health Organization }}</ref> Therefore, given the average age of roughly 1000 years for the CCR5-Δ32 allele, it can be established that HIV-1 did not exert selection pressure on the human population for long enough to achieve the current frequencies.<ref name="Galvani_2005" /> Hence, other pathogens have been suggested as agents of positive selection for CCR5 Δ32, including [[bubonic plague]] (''[[Yersinia pestis]]'') and [[smallpox]] (''[[Variola Major|Variola]]'' [[Variola Major|major]]).
Other data suggest that the allele frequency experienced negative selection pressure as a result of pathogens that became more widespread during Roman expansion.<ref>{{cite journal | vauthors = Faure E, Royer-Carenzi M | title = Is the European spatial distribution of the HIV-1-resistant CCR5-Delta32 allele formed by a breakdown of the pathocenosis due to the historical Roman expansion? | journal = Infection, Genetics and Evolution | volume = 8 | issue = 6 | pages = 864–874 | date = December 2008 | pmid = 18790087 | doi = 10.1016/j.meegid.2008.08.007 | bibcode = 2008InfGE...8..864F | s2cid = 32881202 | url = https://hal.archives-ouvertes.fr/hal-01107403/file/Faure%20Royer-Carenzi%202008D%20revised%20MS%20MEEGID-D-07-00118.pdf }}</ref> The idea that negative selection played a role in the allele's low frequency is also supported by experiments using knockout mice and Influenza A, which demonstrated that the presence of the CCR5 receptor is important for efficient response to a pathogen.<ref>{{cite journal | vauthors = Dawson TC, Beck MA, Kuziel WA, Henderson F, Maeda N | title = Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus | journal = The American Journal of Pathology | volume = 156 | issue = 6 | pages = 1951–1959 | date = June 2000 | pmid = 10854218 | pmc = 1850091 | doi = 10.1016/S0002-9440(10)65068-7 }}</ref><ref>{{cite journal | vauthors = Vargas AE, Cechim G, Correa JF, Gomes PA, Macedo GS, de Medeiros RM, Perotoni G, Rauber R, Villodre ES, Chies JA | title = Pros and cons of a missing chemokine receptor--comments on "Is the European spatial distribution of the HIV-1-resistant CCR5-D32 allele formed by a breakdown of the pathocenosis due to the historical Roman expansion?" by Eric Faure and Manuela Royer-Carenzi (2008) | journal = Infection, Genetics and Evolution: Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases | volume = 9 | issue = 4 | pages = 387–389 | date = July 2009 | pmid = 19472441 | doi = 10.1016/j.meegid.2009.01.001 }}</ref>

== Evidence for a single mutation ==

Several lines of evidence suggest that the CCR5 Δ32 allele evolved only once.<ref name="Galvani_2005" /> First, CCR5 Δ32 has a relatively high frequency in several different European populations but is comparatively absent in Asian, Middle Eastern and American Indian populations,<ref name="Stephens_1998" /> suggesting that a single mutation occurred after divergence of Europeans from their African ancestor.<ref name="Stephens_1998" /><ref name="Dean_1996" /><ref name="O'Brien_1997">{{cite journal | vauthors = O'Brien SJ, Dean M | title = In search of AIDS-resistance genes | journal = Scientific American | volume = 277 | issue = 3 | pages = 44–51 | date = September 1997 | pmid = 9274039 | doi = 10.1038/scientificamerican0997-44 | bibcode = 1997SciAm.277c..44O }}</ref> Second, genetic linkage analysis indicates that the mutation occurs on a homogeneous genetic background, implying that inheritance of the mutation occurred from a common ancestor.<ref name="Libert_1998">{{cite journal | vauthors = Libert F, Cochaux P, Beckman G, Samson M, Aksenova M, Cao A, Czeizel A, Claustres M, de la Rúa C, Ferrari M, Ferrec C, Glover G, Grinde B, Güran S, Kucinskas V, Lavinha J, Mercier B, Ogur G, Peltonen L, Rosatelli C, Schwartz M, Spitsyn V, Timar L, Beckman L, Parmentier M, Vassart G | title = The deltaccr5 mutation conferring protection against HIV-1 in Caucasian populations has a single and recent origin in Northeastern Europe | journal = Human Molecular Genetics | volume = 7 | issue = 3 | pages = 399–406 | date = March 1998 | pmid = 9466996 | doi = 10.1093/hmg/7.3.399 | doi-access = free }}</ref> This was demonstrated by showing that the CCR5 Δ32 allele is in strong linkage disequilibrium with highly polymorphic microsatellites. More than 95% of CCR5 Δ32 chromosomes also carried the IRI3.1-0 allele, while 88% carried the IRI3.2 allele.  By contrast, the microsatellite markers IRI3.1-0 and IRI3.2-0 were found in only 2 or 1.5% of chromosomes carrying a wild-type CCR5 allele.<ref name="Libert_1998" /> This evidence of linkage disequilibrium supports the hypothesis that most, if not all, CCR5 Δ32 alleles arose from a single mutational event.  Finally, the CCR5 Δ32 allele has a unique geographical distribution indicating a single Northern origin followed by migration.  A study measuring allele frequencies in 18 European populations found a North-to-South gradient, with the highest allele frequencies in Finnish and [[Mordvins|Mordvinian]] populations (16%), and the lowest in Sardinia (4%).<ref name="Libert_1998" />

== Positive selection ==

In the absence of selection, a single mutation would take an estimated 127,500 years to rise to a population frequency of 10%.<ref name="Stephens_1998" /> Estimates based on genetic recombination and mutation rates place the age of the allele between 1000 and 2000 years. This discrepancy is a signature of positive selection.

It is estimated that HIV-1 entered the human population in Africa in the early 1900s,<ref name="Keele_2006" /> but symptomatic infections were not reported until the 1980s. The HIV-1 epidemic is therefore far too young to be the source of positive selection that drove the frequency of CCR5 Δ32 from zero to 10% in 2000 years.

=== Protection from bubonic plague ===

Stephens, et al. (1998), suggest that bubonic plague (''Yersinia pestis'') had exerted positive selective pressure on CCR5 Δ32.<ref name="Stephens_1998" /> This hypothesis was based on the timing and severity of the Black Death pandemic, which killed 30% of the European population of all ages between 1346 and 1352.<ref name="McEvedy_1988">{{cite journal | vauthors = McEvedy C | title = The bubonic plague | journal = Scientific American | volume = 258 | issue = 2 | pages = 118–123 | date = February 1988 | pmid = 3055286 | doi = 10.1038/scientificamerican0288-118 | bibcode = 1988SciAm.258b.118M }}</ref> After the Black Death, there were less severe, intermittent epidemics. Individual cities experienced high mortality, but overall mortality in Europe was only a few percent.<ref name="McEvedy_1988" /><ref name="Galley_1998">{{cite book | vauthors = Galley C | title = The Demography of Early Modern Towns: York in the Sixteenth and Seventeenth Centuries | location = London | date = 1998 | publisher = MacMillan }}</ref><ref name="Hatcher_1977">{{cite book | vauthors = Hatcher J | title = Plague, Population, and the English Economy 1348-1530 | location = London | date = 1977 | publisher = MacMillan }}</ref> In 1655-1656 a second pandemic called the "Great Plague" killed 15-20% of London's population.<ref>{{cite web | title = The Great Plague of London, 1665 | url = http://ocp.hul.harvard.edu/contagion/plague.html | website = Contagion, Historical Views of Diseases and Epidemics | publisher = Harvard University | access-date = 2015-03-02 }}</ref><ref>{{Cite web | title = DNA in London Grave May Help Solve Mysteries of the Great Plague | date = 2016-09-08 | url = http://news.nationalgeographic.com/2016/09/bubonic-plague-dna-found-london-black-death | archive-url = https://web.archive.org/web/20160909183423/http://news.nationalgeographic.com/2016/09/bubonic-plague-dna-found-london-black-death/ | url-status = dead | archive-date = 9 September 2016 | access-date = 2016-09-18 }}</ref>{{dubious|reason=Possibly of a part of a region but not the entire continent, surely.|date=March 2020}} Importantly, the plague epidemics were intermittent. Bubonic plague is a zoonotic disease, primarily infecting rodents, spread by fleas, and only occasionally infecting humans.<ref name="Keeling_2000">{{cite journal | vauthors = Keeling MJ, Gilligan CA | title = Bubonic plague: a metapopulation model of a zoonosis | journal = Proceedings. Biological Sciences | volume = 267 | issue = 1458 | pages = 2219–2230 | date = November 2000 | pmid = 11413636 | pmc = 1690796 | doi = 10.1098/rspb.2000.1272 }}</ref> Human-to-human infection of bubonic plague does not occur, though it can occur in pneumonic plague, which infects the lungs.<ref name="Appleby_1980">{{cite journal | vauthors = Appleby AB | title = The disappearance of plague: a continuing puzzle | journal = The Economic History Review | volume = 33 | issue = 2 | pages = 161–173 | year = 1980 | pmid = 11614424 | doi = 10.2307/2595837 | jstor = 2595837 }}</ref> Only when the density of rodents is low are infected fleas forced to feed on alternative hosts such as humans, and under these circumstances a human epidemic may occur.<ref name="Keeling_2000" /> Based on population genetic models, Galvani and Slatkin (2003) argue that the intermittent nature of plague epidemics did not generate a sufficiently strong selective force to drive the allele frequency of CCR5 Δ32 to 10% in Europe.<ref name="Galvani_2003" /> To test this hypothesis, Galvani and Slatkin (2003) modeled the historical selection pressures produced by plague and smallpox.<ref name="Galvani_2003" />

=== Protection from smallpox ===
Plague was modeled according to historical accounts,<ref name="Russel_1948">{{cite book | vauthors = Russel JS | title = British Mediaeval Population | location = Albuquerque | date = 1948 | publisher = University of New Mexico Press }}</ref><ref name="Twigg_1984">{{cite book | vauthors = Twigg G | title = The Black Death: A Biological Reappraisal | location = London | date = 1984 | publisher = Batsfod }}</ref> while age-specific smallpox mortality was gleaned from the age distribution of smallpox burials in York (England) between 1770 and 1812.<ref name="Galley_1998" /> Smallpox preferentially infects young, pre-reproductive members of the population since they are the only individuals who are not immunized or dead from past infection. Because smallpox preferentially kills pre-reproductive members of a population, it generates stronger selective pressure than plague.<ref name="Galvani_2003" /> Unlike plague, smallpox does not have an animal reservoir and is only transmitted from human to human.<ref name="Chapin_1913">{{cite journal | vauthors = Chapin CV | title = Variation in the type of infectious diseases as shown by the history of smallpox in the United States, 1815-1912 | journal = J Infect Dis | volume = 13 | issue = 2 | pages = 171–196 | date = 1913 | doi = 10.1093/infdis/13.2.171 | url = https://zenodo.org/record/1431759 }}</ref><ref name="Fenner_1998">{{cite journal | vauthors = Fenner F | title = Historical vignette: a life with poxviruses and publishers | journal = Advances in Virus Research | volume = 51 | pages = 1–33 | year = 1998 | pmid = 9891584 | doi = 10.1016/S0065-3527(08)60782-4 | isbn = 978-0-12-039851-5 }}</ref> The authors calculated that if plague were selecting for CCR5 Δ32, the frequency of the allele would still be less than 1%, while smallpox has exerted a selective force sufficient to reach 10%.

The hypothesis that smallpox exerted positive selection for CCR5 Δ32 is also biologically plausible, since poxviruses, like HIV, enter white blood cells using chemokine receptors.<ref name="Lalani_1999">{{cite journal | vauthors = Lalani AS, Masters J, Zeng W, Barrett J, Pannu R, Everett H, Arendt CW, McFadden G | title = Use of chemokine receptors by poxviruses | journal = Science | location = New York, N.Y. | volume = 286 | issue = 5446 | pages = 1968–1971 | date = December 1999 | pmid = 10583963 | doi = 10.1126/science.286.5446.1968 }}</ref> By contrast, ''Yersinia pestis'' is a bacterium with a very different biology.

Although Europeans are the only group to have subpopulations with a high frequency of CCR5 Δ32, they are not the only population that has been subject to selection by smallpox, which had a worldwide distribution before it was declared eradicated in 1980.  The earliest unmistakable descriptions of smallpox appear in the 5th century A.D. in China, the 7th century A.D. in India and the Mediterranean, and the 10th century A.D. in southwestern Asia.<ref name="Fenner_1998" /> By contrast, the ''CCR5 Δ''32 mutation is found only in European, West Asian, and North African populations.<ref name="Novembre_2005">{{cite journal | vauthors = Novembre J, Galvani AP, Slatkin M | title = The geographic spread of the CCR5 Delta32 HIV-resistance allele | journal = PLOS Biology | volume = 3 | issue = 11 | pages = e339 | date = November 2005 | pmid = 16216086 | pmc = 1255740 | doi = 10.1371/journal.pbio.0030339 | doi-access = free }}</ref> The anomalously high frequency of CCR5 Δ32 in these populations appears to require both a unique origin in Northern Europe and subsequent selection by smallpox.

== Potential costs ==
CCR5 Δ32 can be beneficial to the host in some infections (e.g., HIV-1, possibly smallpox), but detrimental in others (e.g., [[tick-borne encephalitis]], [[West Nile virus]]).  Whether CCR5 function is helpful or harmful in the context of a given infection depends on a complex interplay between the immune system and the pathogen.<ref>{{cite journal | vauthors = OBrien SJ | title = Legacy of a magic gene-''CCR5-'''∆'''32'': From discovery to clinical benefit in a generation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 121 | issue = 12 | pages = e2321907121 | date = March 2024 | pmid = 38457490 | pmc = 10962972 | doi = 10.1073/pnas.2321907121 | bibcode = 2024PNAS..12121907O }}</ref>

In general, research suggests that the CCR5 Δ32 mutation may play a deleterious role in post-infection inflammatory processes, which can injure tissue and create further pathology.<ref name="Klein_2008">{{cite journal | vauthors = [[Robyn S. Klein|Klein RS]] | title = A moving target: the multiple roles of CCR5 in infectious diseases | journal = The Journal of Infectious Diseases | volume = 197 | issue = 2 | pages = 183–186 | date = January 2008 | pmid = 18179384 | doi = 10.1086/524692 | doi-access = free }}</ref> The best evidence for this proposed antagonistic pleiotropy is found in [[flavivirus]] infections. In general many viral infections are asymptomatic or produce only mild symptoms in the vast majority of the population. However, certain unlucky individuals experience a particularly destructive clinical course, which is otherwise unexplained but appears to be genetically mediated. Patients homozygous for CCR5 Δ32 were found to be at higher risk for a neuroinvasive form of tick-borne encephalitis (caused by [[Tick-borne encephalitis virus|a flavivirus]]).<ref name="Kindberg_2008">{{cite journal | vauthors = Kindberg E, Mickiene A, Ax C, Akerlind B, Vene S, Lindquist L, Lundkvist A, Svensson L | title = A deletion in the chemokine receptor 5 (CCR5) gene is associated with tickborne encephalitis | journal = The Journal of Infectious Diseases | volume = 197 | issue = 2 | pages = 266–269 | date = January 2008 | pmid = 18179389 | doi = 10.1086/524709 | doi-access = free }}</ref> In addition, functional CCR5 may be required to prevent symptomatic disease after infection with West Nile virus, another flavivirus; CCR5 Δ32 was associated with early symptom development and more pronounced clinical manifestations after infection with West Nile virus.<ref name="Lim_2008">{{cite journal | vauthors = Lim JK, Louie CY, Glaser C, Jean C, Johnson B, Johnson H, McDermott DH, Murphy PM | title = Genetic deficiency of chemokine receptor CCR5 is a strong risk factor for symptomatic West Nile virus infection: a meta-analysis of 4 cohorts in the US epidemic | journal = The Journal of Infectious Diseases | volume = 197 | issue = 2 | pages = 262–265 | date = January 2008 | pmid = 18179388 | doi = 10.1086/524691 | doi-access = free }}</ref>

This finding in humans confirmed a previously observed experiment in an animal model of CCR5 Δ32 homozygosity.  After infection with West Nile virus, CCR5 Δ32 mice had markedly increased viral titers in the central nervous system and had increased mortality<ref name="Glass_2005">{{cite journal | vauthors = Glass WG, Lim JK, Cholera R, Pletnev AG, Gao JL, Murphy PM | title = Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection | journal = The Journal of Experimental Medicine | volume = 202 | issue = 8 | pages = 1087–1098 | date = October 2005 | pmid = 16230476 | pmc = 2213214 | doi = 10.1084/jem.20042530 }}</ref> compared with that of wild-type mice, thus suggesting that CCR5 expression was necessary to mount a strong host defense against West Nile virus.

== Medical applications ==

A genetic approach involving intrabodies that block CCR5 expression has been proposed as a treatment for [[HIV-1]] infected individuals.<ref name="Steinberger_2000">{{cite journal | vauthors = Steinberger P, Andris-Widhopf J, Bühler B, Torbett BE, Barbas CF | title = Functional deletion of the CCR5 receptor by intracellular immunization produces cells that are refractory to CCR5-dependent HIV-1 infection and cell fusion | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 2 | pages = 805–810 | date = January 2000 | pmid = 10639161 | pmc = 15412 | doi = 10.1073/pnas.97.2.805 | doi-access = free | bibcode = 2000PNAS...97..805S }}</ref> When T-cells modified so they no longer express CCR5 were mixed with unmodified T-cells expressing CCR5 and then challenged by infection with HIV-1, the modified T-cells that do not express CCR5 eventually take over the culture, as HIV-1 kills the non-modified T-cells. This same method might be used ''in vivo'' to establish a virus-resistant cell pool in infected individuals.<ref name="Steinberger_2000" />

This hypothesis was tested in an AIDS patient who had also developed [[myeloid leukemia]], and was treated with [[chemotherapy]] to suppress the cancer.  A [[hematopoietic stem cell transplantation|bone marrow transplant]] containing [[stem cell]]s from a matched donor was then used to restore the immune system.  However, the transplant was performed from a donor with 2 copies of CCR5-Δ32 mutation gene.  After 600 days, the patient was healthy and had undetectable levels of HIV in the blood and in examined brain and rectal tissues.<ref name="Hutter_2009">{{cite journal | vauthors = Hütter G, Nowak D, Mossner M, Ganepola S, Müssig A, Allers K, Schneider T, Hofmann J, Kücherer C, Blau O, Blau IW, Hofmann WK, Thiel E | title = Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation | journal = The New England Journal of Medicine | volume = 360 | issue = 7 | pages = 692–698 | date = February 2009 | pmid = 19213682 | doi = 10.1056/NEJMoa0802905 }}</ref><ref name="urlA Doctor, a Mutation and a Potential Cure for AIDS - WSJ.com">{{cite news | vauthors = Schoofs M | title = A Doctor, a Mutation and a Potential Cure for AIDS | date = 7 November 2008 | url = https://www.wsj.com/articles/SB122602394113507555 | work = [[The Wall Street Journal]] | access-date = 15 December 2010 }}</ref> Before the transplant, low levels of [[HIV tropism|HIV X4]], which does not use the CCR5 receptor, were also detected. Following the transplant, however, this type of HIV was not detected either.<ref name="Hutter_2009" /> However, this outcome is consistent with the observation that cells expressing the CCR5-Δ32 variant protein lack both the CCR5 and [[CXCR4]] receptors on their surfaces, thereby conferring resistance to a broad range of HIV variants including HIVX4.<ref name="Agrawal_2004">{{cite journal | vauthors = Agrawal L, Lu X, Qingwen J, VanHorn-Ali Z, Nicolescu IV, McDermott DH, Murphy PM, Alkhatib G | title = Role for CCR5Delta32 protein in resistance to R5, R5X4, and X4 human immunodeficiency virus type 1 in primary CD4+ cells | journal = Journal of Virology | volume = 78 | issue = 5 | pages = 2277–2287 | date = March 2004 | pmid = 14963124 | pmc = 369216 | doi = 10.1128/JVI.78.5.2277-2287.2004 }}</ref>  After over six years, the patient has maintained the resistance to HIV and has been pronounced cured of the HIV infection.<ref name="Allers_2011">{{cite journal | vauthors = Allers K, Hütter G, Hofmann J, Loddenkemper C, Rieger K, Thiel E, Schneider T | title = Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation | journal = Blood | volume = 117 | issue = 10 | pages = 2791–2799 | date = March 2011 | pmid = 21148083 | doi = 10.1182/blood-2010-09-309591 }}</ref>

Enrollment of HIV-positive patients in a clinical trial was started in 2009 in which the patients' cells were genetically modified with a [[zinc finger nuclease]] to carry the CCR5-Δ32 trait and then reintroduced into the body as a potential HIV treatment.<ref>{{cite web | title = Autologous T-Cells Genetically Modified at the CCR5 Gene by Zinc Finger Nucleases SB-728 for HIV (Zinc-Finger) | date = 9 December 2009 | url = http://clinicaltrials.gov/ct2/show/NCT00842634?term=806383&rank=1 | publisher = U.S. National Institutes of Health | access-date = 30 December 2009 }}</ref><ref name="urlZinc Fingers Could Be Key to Reviving Gene Therapy - NYTimes.com">{{cite news | vauthors = Wade N | title = Zinc Fingers Could Be Key to Reviving Gene Therapy | date = 28 December 2009 | url = https://www.nytimes.com/2009/12/29/health/research/29zinc.html | work = [[The New York Times]] | access-date = 30 December 2009 }}</ref>  Results reported in 2014 were promising.<ref name="Tebas_2014">{{cite journal | vauthors = Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, Spratt SK, Surosky RT, Giedlin MA, Nichol G, Holmes MC, Gregory PD, Ando DG, Kalos M, Collman RG, Binder-Scholl G, Plesa G, Hwang WT, Levine BL, June CH | title = Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV | journal = The New England Journal of Medicine | volume = 370 | issue = 10 | pages = 901–910 | date = March 2014 | pmid = 24597865 | pmc = 4084652 | doi = 10.1056/NEJMoa1300662 }}</ref>

Inspired by the first person to be cured of HIV, [[The Berlin Patient]], StemCyte began collaborations with [[cord blood bank]]s worldwide to systematically screen [[umbilical cord blood]] samples for the CCR5 mutation beginning in 2011.<ref name="Plan launched to find HIV cure">{{cite journal | vauthors = Corbyn Z | title = Plan launched to find HIV cure | journal = Lancet | location = London, England | volume = 380 | issue = 9838 | pages = 203–204 | date = July 2012 | pmid = 22826833 | doi = 10.1016/s0140-6736(12)61199-4 | s2cid = 34773481 | doi-access = free }}</ref><ref name="CCR5Δ32/Δ32 HIV-resistant cord blood">{{cite journal | vauthors = Gonzalez G, Park S, Chen D, Armitage S, Shpall E, Behringer R | title = Identification and frequency of CCR5Δ32/Δ32 HIV-resistant cord blood units from Houston area hospitals | journal = HIV Medicine | volume = 12 | issue = 8 | pages = 481–486 | date = September 2011 | pmid = 21375684 | pmc = 4021858 | doi = 10.1111/j.1468-1293.2010.00911.x }}</ref><ref name="Petz_2015">{{cite journal | vauthors = Petz LD, Burnett JC, Li H, Li S, Tonai R, Bakalinskaya M, Shpall EJ, Armitage S, Kurtzberg J, Regan DM, Clark P, Querol S, Gutman JA, Spellman SR, Gragert L, Rossi JJ | title = Progress toward curing HIV infection with hematopoietic cell transplantation | journal = Stem Cells and Cloning: Advances and Applications | volume = 8 | pages = 109–116 | year = 2015 | pmid = 26251620 | pmc = 4524463 | doi = 10.2147/SCCAA.S56050 | doi-access = free }}</ref>

In November 2018, [[He Jiankui|Jiankui He]] announced that he had edited two human embryos, to attempt to disable the gene for CCR5, which codes for a receptor that HIV uses to enter cells.  He said that twin girls, [[Lulu and Nana]], had been born a few weeks earlier, and that the girls still carried functional copies of CCR5 along with disabled CCR5 ([[mosaicism]]), hence being still vulnerable to HIV.  The work was widely condemned as unethical, dangerous, and premature.<ref>{{cite news | vauthors = Begley S | title = Amid uproar, Chinese scientist defends creating gene-edited babies | date = 28 November 2018 | url = https://www.statnews.com/2018/11/28/chinese-scientist-defends-creating-gene-edited-babies/ | work = STAT }}</ref><ref>{{cite web | vauthors = Collins FS | title = Statement on Claim of First Gene-Edited Babies by Chinese Researcher | date = 28 November 2018 | url = https://www.nih.gov/about-nih/who-we-are/nih-director/statements/statement-claim-first-gene-edited-babies-chinese-researcher | work = National Institutes of Health (NIH) | publisher = U.S. Department of Health and Human Services }}</ref>

== References ==
{{Reflist}}

[[Category:Chemokine receptors]]