CCR5

CCR5 is predominantly expressed on T cells, macrophages, dendritic cells, eosinophils, microglia and a subpopulation of either breast or prostate cancer cells.{{cite journal | vauthors = Velasco-Velázquez M, Jiao X, De La Fuente M, Pestell TG, Ertel A, Lisanti MP, Pestell RG | title = CCR5 antagonist blocks metastasis of basal breast cancer cells | journal = Cancer Research | volume = 72 | issue = 15 | pages = 3839–3850 | date = August 2012 | pmid = 22637726 | doi = 10.1158/0008-5472.CAN-11-3917 | doi-access = free }}{{cite journal | vauthors = Sicoli D, Jiao X, Ju X, Velasco-Velazquez M, Ertel A, Addya S, Li Z, Andò S, Fatatis A, Paudyal B, Cristofanilli M, Thakur ML, Lisanti MP, Pestell RG | title = CCR5 receptor antagonists block metastasis to bone of v-Src oncogene-transformed metastatic prostate cancer cell lines | journal = Cancer Research | volume = 74 | issue = 23 | pages = 7103–7114 | date = December 2014 | pmid = 25452256 | pmc = 4294544 | doi = 10.1158/0008-5472.CAN-14-0612 }} The expression of CCR5 is selectively induced during the cancer transformation process and is not expressed in normal breast or prostate epithelial cells. Approximately 50% of human breast cancer expressed CCR5, primarily in triple negative breast cancer.

File:CCR5 Primary Protein Sequence.png

CCR5, or CC chemokine receptor 5, is a member of the class A G protein-coupled receptor (GPCR) family characterized by a canonical structure comprising seven transmembrane (7TM) α-helices (labeled I–VII), which are interconnected by three extracellular loops (ECL1–3) and three intracellular loops (ICL1–3).{{cite journal | vauthors = Tan Q, Zhu Y, Li J, Chen Z, Han GW, Kufareva I, Li T, Ma L, Fenalti G, Li J, Zhang W, Xie X, Yang H, Jiang H, Cherezov V, Liu H, Stevens RC, Zhao Q, Wu B | title = Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex | journal = Science (New York, N.Y.) | volume = 341 | issue = 6152 | pages = 1387–90 | date = September 2013 | pmid = 24030490 | pmc = 3819204 | doi = 10.1126/science.1241475 | bibcode = 2013Sci...341.1387T | url = }}{{cite journal | vauthors = McNicholl JM, Smith DK, Qari SH, Hodge T | title = Host genes and HIV: the role of the chemokine receptor gene CCR5 and its allele | journal = Emerging Infectious Diseases | volume = 3 | issue = 3 | pages = 261–71 | date = 1997 | pmid = 9284370 | pmc = 2627644 | doi = 10.3201/eid0303.970302 | url = }} The largest extracellular loop, ECL2, adopts a β-hairpin conformation stabilized by disulfide bonds: one links Cys101 in helix III with Cys178 in ECL2, and another connects Cys20 at the N-terminus to Cys269 in helix VII, constraining the receptor’s extracellular architecture. The N-terminal region and extracellular loops are critical for ligand (chemokine) recognition and binding, with the N-terminus forming specific interactions with chemokines such as MIP-1α and RANTES.{{cite journal | vauthors = Zhang H, Chen K, Tan Q, Shao Q, Han S, Zhang C, Yi C, Chu X, Zhu Y, Xu Y, Zhao Q, Wu B | title = Structural basis for chemokine recognition and receptor activation of chemokine receptor CCR5 | journal = Nature Communications | volume = 12 | issue = 1 | pages = 4151 | date = July 2021 | pmid = 34230484 | pmc = 8260604 | doi = 10.1038/s41467-021-24438-5 | bibcode = 2021NatCo..12.4151Z | url = }} The transmembrane helices form a deep ligand-binding pocket, accommodating both endogenous chemokines and small molecule inhibitors like maraviroc, with key residues such as Glu283 and Tyr251 mediating ligand interactions through hydrogen bonds and salt bridges. On the intracellular side, helix VI undergoes conformational changes upon activation to facilitate G protein coupling, while helix VIII forms a short α-helix unique to CCR5 compared to related receptors like CXCR4. The overall architecture, including the arrangement of helices and loops, underpins CCR5’s roles in immune signaling and as a co-receptor for HIV-1 entry.

The CCR5 protein belongs to the beta chemokine receptors family of integral membrane proteins.{{cite web | url = http://ghr.nlm.nih.gov/gene=ccr5 | title = CCR5 - chemokine (C-C motif) receptor 5 (gene/pseudogene) | work = Genetics Home Reference | access-date = 30 August 2009 | archive-date = 24 September 2009 | archive-url = https://web.archive.org/web/20090924213403/http://ghr.nlm.nih.gov/gene%3Dccr5 | url-status = dead }}{{cite journal | vauthors = Samson M, Labbe O, Mollereau C, Vassart G, Parmentier M | title = Molecular cloning and functional expression of a new human CC-chemokine receptor gene | journal = Biochemistry | volume = 35 | issue = 11 | pages = 3362–3367 | date = March 1996 | pmid = 8639485 | doi = 10.1021/bi952950g }} It is a G protein–coupled receptor which functions as a chemokine receptor in the CC chemokine group.

CCR5's cognate ligands include CCL3, CCL4 (also known as MIP 1α and 1β, respectively), and CCL3L1.{{cite journal | vauthors = Miyakawa T, Obaru K, Maeda K, Harada S, Mitsuya H | title = Identification of amino acid residues critical for LD78beta, a variant of human macrophage inflammatory protein-1alpha, binding to CCR5 and inhibition of R5 human immunodeficiency virus type 1 replication | journal = The Journal of Biological Chemistry | volume = 277 | issue = 7 | pages = 4649–4655 | date = February 2002 | pmid = 11734558 | doi = 10.1074/jbc.M109198200 | doi-access = free }} CCR5 furthermore interacts with CCL5 (a chemotactic cytokine protein also known as RANTES).{{cite journal | vauthors = Struyf S, Menten P, Lenaerts JP, Put W, D'Haese A, De Clercq E, Schols D, Proost P, Van Damme J | title = Diverging binding capacities of natural LD78beta isoforms of macrophage inflammatory protein-1alpha to the CC chemokine receptors 1, 3 and 5 affect their anti-HIV-1 activity and chemotactic potencies for neutrophils and eosinophils | journal = European Journal of Immunology | volume = 31 | issue = 7 | pages = 2170–2178 | date = July 2001 | pmid = 11449371 | doi = 10.1002/1521-4141(200107)31:7<2170::AID-IMMU2170>3.0.CO;2-D | doi-access = free }}{{cite journal | vauthors = Slimani H, Charnaux N, Mbemba E, Saffar L, Vassy R, Vita C, Gattegno L | title = Interaction of RANTES with syndecan-1 and syndecan-4 expressed by human primary macrophages | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1617 | issue = 1–2 | pages = 80–88 | date = October 2003 | pmid = 14637022 | doi = 10.1016/j.bbamem.2003.09.006 | doi-access = free }}{{cite journal | vauthors = Proudfoot AE, Fritchley S, Borlat F, Shaw JP, Vilbois F, Zwahlen C, Trkola A, Marchant D, Clapham PR, Wells TN | title = The BBXB motif of RANTES is the principal site for heparin binding and controls receptor selectivity | journal = The Journal of Biological Chemistry | volume = 276 | issue = 14 | pages = 10620–10626 | date = April 2001 | pmid = 11116158 | doi = 10.1074/jbc.M010867200 | doi-access = free }}

It is likely that CCR5 plays a role in inflammatory responses to infection, though its exact role in normal immune function is unclear. Regions of this protein are also crucial for chemokine ligand binding, the functional response of the receptor, and HIV co-receptor activity.{{cite journal | vauthors = Barmania F, Pepper MS | title = C-C chemokine receptor type five (CCR5): An emerging target for the control of HIV infection | journal = Applied & Translational Genomics | volume = 2 | issue = a | pages = 3–16 | date = December 2013 | pmid = 27942440 | pmc = 5133339 | doi = 10.1016/j.atg.2013.05.004 }}

Modulation of CCR5 activity contributes to a non-pathogenic course of infection with simian immunodeficiency virus (SIV) in several African non-human primate species that are long-term natural hosts of SIV and avoid immunodeficiency upon the infection.{{Cite journal| vauthors = Jasinska AJ, Pandrea I, Apetrei C |date=27 January 2022|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|doi=10.3389/fimmu.2022.835994|pmid=35154162|issn=1664-3224|pmc=8829453|doi-access=free}} These regulatory mechanisms include: genetic deletions that abrogate cell surface expression of CCR5,{{cite journal | vauthors = Chen Z, Kwon D, Jin Z, Monard S, Telfer P, Jones MS, Lu CY, Aguilar RF, Ho DD, Marx PA | title = Natural infection of a homozygous delta24 CCR5 red-capped mangabey with an R2b-tropic simian immunodeficiency virus | journal = The Journal of Experimental Medicine | volume = 188 | issue = 11 | pages = 2057–2065 | date = December 1998 | pmid = 9841919 | doi = 10.1084/jem.188.11.2057 | pmc = 2212380 }} downregulation of CCR5 on the surface of CD4+ T cells, in particular on memory cells,{{cite journal | vauthors = Paiardini M, Cervasi B, Reyes-Aviles E, Micci L, Ortiz AM, Chahroudi A, Vinton C, Gordon SN, Bosinger SE, Francella N, Hallberg PL, Cramer E, Schlub T, Chan ML, Riddick NE, Collman RG, Apetrei C, Pandrea I, Else J, Munch J, Kirchhoff F, Davenport MP, Brenchley JM, Silvestri G | title = Low levels of SIV infection in sooty mangabey central memory CD⁴⁺ T cells are associated with limited CCR5 expression | journal = Nature Medicine | volume = 17 | issue = 7 | pages = 830–836 | date = June 2011 | pmid = 21706028 | doi = 10.1038/nm.2395 | pmc = 3253129 }} and delayed onset of CCR5 expression on the CD4+ T cells during development.{{cite journal | vauthors = Ma D, Jasinska AJ, Feyertag F, Wijewardana V, Kristoff J, He T, Raehtz K, Schmitt CA, Jung Y, Cramer JD, Dione M, Antonio M, Tracy R, Turner T, Robertson DL, Pandrea I, Freimer N, Apetrei C | title = Factors associated with siman immunodeficiency virus transmission in a natural African nonhuman primate host in the wild | journal = Journal of Virology | volume = 88 | issue = 10 | pages = 5687–5705 | date = May 2014 | pmid = 24623416 | pmc = 4019088 | doi = 10.1128/JVI.03606-13 }}{{cite journal | vauthors = Pandrea I, Onanga R, Souquiere S, Mouinga-Ondéme A, Bourry O, Makuwa M, Rouquet P, Silvestri G, Simon F, Roques P, Apetrei C | title = Paucity of CD4+ CCR5+ T cells may prevent transmission of simian immunodeficiency virus in natural nonhuman primate hosts by breast-feeding | journal = Journal of Virology | volume = 82 | issue = 11 | pages = 5501–5509 | date = June 2008 | pmid = 18385229 | doi = 10.1128/JVI.02555-07 | pmc = 2395173 }}

{{further|HIV tropism|Entry inhibitor}}

File:HIV attachment.gif

HIV-1 most commonly uses the chemokine receptors CCR5 and/or CXCR4 as co-receptors to enter target immunological cells.{{cite journal | vauthors = Murphy PM | title = Viral exploitation and subversion of the immune system through chemokine mimicry | journal = Nature Immunology | volume = 2 | issue = 2 | pages = 116–122 | date = February 2001 | pmid = 11175803 | doi = 10.1038/84214 | s2cid = 29364407 | doi-access = free }} These receptors are located on the surface of host immune cells whereby they provide a method of entry for the HIV-1 virus to infect the cell.{{cite journal | vauthors = Alkhatib G | title = The biology of CCR5 and CXCR4 | journal = Current Opinion in HIV and AIDS | volume = 4 | issue = 2 | pages = 96–103 | date = March 2009 | pmid = 19339947 | pmc = 2718543 | doi = 10.1097/COH.0b013e328324bbec }} The HIV-1 envelope glycoprotein structure is essential in enabling the viral entry of HIV-1 into a target host cell. The envelope glycoprotein structure consists of two protein subunits cleaved from a Gp160 protein precursor encoded for by the HIV-1 env gene: the Gp120 external subunit and the Gp41 transmembrane subunit. This envelope glycoprotein structure is arranged into a spike-like structure located on the surface of the virion and consists of a trimer of Gp120-Gp41 hetero-dimers. The Gp120 envelope protein is a chemokine mimic. Though it lacks the unique structure of a chemokine, it is still capable of binding to the CCR5 and CXCR4 chemokine receptors. During HIV-1 infection, the Gp120 envelope glycoprotein subunit binds to a CD4 glycoprotein and a HIV-1 co-receptor expressed on a target cell, forming a heterotrimeric complex. The formation of this complex stimulates the release of a fusogenic peptide, causing the viral membrane to fuse with the membrane of the target host cell. Because binding to CD4 alone can sometimes result in gp120 shedding, gp120 must next bind to co-receptor CCR5 in order for fusion to proceed. The tyrosine-sulfated amino terminus of this co-receptor is the "essential determinant" of binding to the gp120 glycoprotein.{{cite web | url = http://www.prn.org/index.php/management/article/ccr5_inhibitors_hiv_86 | title = CCR5 Inhibitors and HIV }} The co-receptor also recognizes the V1-V2 region of gp120 and the bridging sheet (an antiparallel, 4-stranded β sheet that connects the inner and outer domains of gp120). The V1-V2 stem can influence "co-receptor usage through its peptide composition as well as by the degree of N-linked glycosylation." Unlike V1-V2 however, the V3 loop is highly variable and thus is the most important determinant of co-receptor specificity. The normal ligands for this receptor, RANTES, MIP-1β, and MIP-1α, are able to suppress HIV-1 infection in vitro.{{cite journal | vauthors = Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P | title = Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells | journal = Science | volume = 270 | issue = 5243 | pages = 1811–1815 | date = December 1995 | pmid = 8525373 | doi = 10.1126/science.270.5243.1811 | bibcode = 1995Sci...270.1811C }} In individuals infected with HIV, CCR5-using viruses are the predominant species isolated during the early stages of viral infection,{{cite journal | vauthors = Anderson J, Akkina R | title = Complete knockdown of CCR5 by lentiviral vector-expressed siRNAs and protection of transgenic macrophages against HIV-1 infection | journal = Gene Therapy | volume = 14 | issue = 17 | pages = 1287–1297 | date = September 2007 | pmid = 17597795 | doi = 10.1038/sj.gt.3302958 | doi-access = free }} suggesting that these viruses may have a selective advantage during transmission or the acute phase of disease. Moreover, at least half of all infected individuals harbor only CCR5-using viruses throughout the course of infection.

CCR5 is the primary co-receptor used by gp120 sequentially with CD4. This bind results in gp41, the other protein product of gp160, released from its metastable conformation and inserted into the membrane of the host cell. Although it has not been confirmed, binding of gp120-CCR5 involves two crucial steps: 1) The tyrosine-sulfated amino terminus of this co-receptor is an "essential determinant" of binding to gp120 (as stated previously) 2) Following step 1., there must be reciprocal action (synergy, intercommunication) between gp120 and the CCR5 transmembrane domains.

CCR5 is essential for the spread of the R5-strain of the HIV-1 virus.{{cite journal | vauthors = Lieberman-Blum SS, Fung HB, Bandres JC | title = Maraviroc: a CCR5-receptor antagonist for the treatment of HIV-1 infection | journal = Clinical Therapeutics | volume = 30 | issue = 7 | pages = 1228–1250 | date = July 2008 | pmid = 18691983 | doi = 10.1016/s0149-2918(08)80048-3 }} Knowledge of the mechanism by which this strain of HIV-1 mediates infection has prompted research into the development of therapeutic interventions to block CCR5 function.{{cite journal | vauthors = Nazari R, Joshi S | title = CCR5 as target for HIV-1 gene therapy | journal = Current Gene Therapy | volume = 8 | issue = 4 | pages = 264–272 | date = August 2008 | pmid = 18691022 | doi = 10.2174/156652308785160674 }} A number of new experimental HIV drugs, called CCR5 receptor antagonists, have been designed to interfere with binding between the Gp120 envelope protein and the HIV co-receptor CCR5. These experimental drugs include PRO140 (CytoDyn), Vicriviroc (Phase III trials were cancelled in July 2010) (Schering Plough), Aplaviroc (GW-873140) (GlaxoSmithKline) and Maraviroc (UK-427857) (Pfizer). Maraviroc was approved for use by the FDA in August 2007. It is the only one thus far approved by the FDA for clinical use, thus becoming the first CCR5 inhibitor. A problem of this approach is that, while CCR5 is the major co-receptor by which HIV infects cells, it is not the only such co-receptor. It is possible that under selective pressure HIV will evolve to use another co-receptor. However, examination of viral resistance to AD101, molecular antagonist of CCR5, indicated that resistant viruses did not switch to another co-receptor (CXCR4), but persisted in using CCR5: they either bound to alternative domains of CCR5 or to the receptor at a higher affinity. However, because there is still another co-receptor available, it is probable that lacking the CCR5 gene does not make one immune to the virus; it would simply be more challenging for the individual to contract it. Also, the virus still has access to CD4. Unlike CCR5, which is not required (as evidenced by those living healthy lives even when lacking the gene as a result of the delta32 mutation), CD4 is critical in the body's immune defense system.{{cite web | vauthors = Starr DB |url=https://www.thetech.org/ask-a-geneticist/articles/2009/ask336/ |title=Are any people genetically predisposed to being immune to HIV? |date=19 November 2009 |website=The Tech Interactive |series=Ask a Geneticist |access-date=5 August 2024}} Even without the availability of either co-receptor (even CCR5), the virus can still invade cells if gp41 were to go through an alteration (including its cytoplasmic tail) that resulted in the independence of CD4 without the need of CCR5 and/or CXCR4 as a doorway.{{cite journal | vauthors = Taylor BM, Foulke JS, Flinko R, Heredia A, DeVico A, Reitz M | title = An alteration of human immunodeficiency virus gp41 leads to reduced CCR5 dependence and CD4 independence | journal = Journal of Virology | volume = 82 | issue = 11 | pages = 5460–5471 | date = June 2008 | pmid = 18353949 | pmc = 2395218 | doi = 10.1128/JVI.01049-07 }}

CCR5 inhibitors blocked the migration and metastasis of breast and prostate cancer cells that expressed CCR5, suggesting that CCR5 may function as a new therapeutic target.{{cite journal | vauthors = Velasco-Velázquez M, Xolalpa W, Pestell RG | title = The potential to target CCL5/CCR5 in breast cancer | journal = Expert Opinion on Therapeutic Targets | volume = 18 | issue = 11 | pages = 1265–1275 | date = November 2014 | pmid = 25256399 | doi = 10.1517/14728222.2014.949238 | s2cid = 7976259 }} Recent studies suggest that CCR5 is expressed in a subset of cancer cells with characteristics of cancer stem cells, which are known to drive therapy resistance, and that CCR5 inhibitors enhanced the number of cells killed by current chemotherapy.{{cite journal | vauthors = Jiao X, Velasco-Velázquez MA, Wang M, Li Z, Rui H, Peck AR, Korkola JE, Chen X, Xu S, DuHadaway JB, Guerrero-Rodriguez S, Addya S, Sicoli D, Mu Z, Zhang G, Stucky A, Zhang X, Cristofanilli M, Fatatis A, Gray JW, Zhong JF, Prendergast GC, Pestell RG | title = CCR5 Governs DNA Damage Repair and Breast Cancer Stem Cell Expansion | journal = Cancer Research | volume = 78 | issue = 7 | pages = 1657–1671 | date = April 2018 | pmid = 29358169 | pmc = 6331183 | doi = 10.1158/0008-5472.CAN-17-0915 }}

Expression of CCR5 is induced in breast and prostate epithelial cells upon transformation. The induction of CCR5 expression promotes cellular invasion, migration, and metastasis. The induction of metastasis involves homing to the metastatic site. CCR5 inhibitors including maraviroc and leronlimab have been shown to block lung metastasis of human breast cancer cell lines.{{cite journal | vauthors = Jiao X, Wang M, Zhang Z, Li Z, Ni D, Ashton AW, Tang HY, Speicher DW, Pestell RG | title = Leronlimab, a humanized monoclonal antibody to CCR5, blocks breast cancer cellular metastasis and enhances cell death induced by DNA damaging chemotherapy.| journal = Breast Cancer Research | volume = 23 | issue = 1 | pages = 11 | date = Jan 2021 | pmid = 33485378 | pmc = 7825185 | doi = 10.1186/s13058-021-01391-1 | doi-access = free }} In preclinical studies of immune competent mice CCR5 inhibitors blocked metastasis to the bones and brain. CCR5 inhibitors also reduce the infiltration of tumor associated macrophages.{{cite journal | vauthors = Frankenberger C, Rabe D, Bainer R, Sankarasharma D, Chada K, Krausz T, Gilad Y, Becker L, Rosner MR | title = Metastasis Suppressors Regulate the Tumor Microenvironment by Blocking Recruitment of Prometastatic Tumor-Associated Macrophages | journal = Cancer Research | volume = 75 | issue = 19 | pages = 4063–4073 | date = October 2015 | pmid = 26238785 | pmc = 4592465 | doi = 10.1158/0008-5472.CAN-14-3394 }} A Phase 1 clinical study of a CCR5 inhibitor in heavily pretreated patients with metastatic colon cancer demonstrated an objective clinical response and reduction in metastatic tumor burden.{{cite journal | vauthors = Halama N, Zoernig I, Berthel A, Kahlert C, Klupp F, Suarez-Carmona M, Suetterlin T, Brand K, Krauss J, Lasitschka F, Lerchl T, Luckner-Minden C, Ulrich A, Koch M, Weitz J, Schneider M, Buechler MW, Zitvogel L, Herrmann T, Benner A, Kunz C, Luecke S, Springfeld C, Grabe N, Falk CS, Jaeger D | title = Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients | journal = Cancer Cell | volume = 29 | issue = 4 | pages = 587–601 | date = April 2016 | pmid = 27070705 | doi = 10.1016/j.ccell.2016.03.005 | doi-access = free }}

Increased levels of CCR5 are part of the inflammatory response to stroke and death. Blocking CCR5 with Maraviroc (a drug approved for HIV) may enhance recovery after stroke.{{cite web | url = https://www.science.org/content/article/hiv-drug-could-improve-recovery-after-stroke | title = HIV drug could improve recovery after stroke | website = ScienceMag| access-date = 22 February 2019| date = 21 February 2019 }}{{cite journal | vauthors = Joy MT, Ben Assayag E, Shabashov-Stone D, Liraz-Zaltsman S, Mazzitelli J, Arenas M, Abduljawad N, Kliper E, Korczyn AD, Thareja NS, Kesner EL, Zhou M, Huang S, Silva TK, Katz N, Bornstein NM, Silva AJ, Shohami E, Carmichael ST | title = CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury | journal = Cell | volume = 176 | issue = 5 | pages = 1143–1157.e13 | date = February 2019 | pmid = 30794775 | pmc = 7259116 | doi = 10.1016/j.cell.2019.01.044 | doi-access = free }}

In the developing brain, chemokine receptors such as CCR5 influence neuronal migration and connection. After stroke, they seem to decrease the number of connection sites on neurons near the damage.

{{main|CCR5-Δ32}}

{{See also|Chemokine receptor#Selective pressures on Chemokine receptor 5 (CCR5)|l1=Selective pressures on Chemokine receptor 5 (CCR5)}}

CCR5-Δ32 is a genetic variant characterized by a 32-base-pair deletion in the CCR5 gene, resulting in a nonfunctional receptor that prevents HIV-1 from entering immune cells.{{cite journal | vauthors = Ni J, Wang D, Wang S | title = The CCR5-Delta32 Genetic Polymorphism and HIV-1 Infection Susceptibility: a Meta-analysis | journal = Open Medicine (Warsaw, Poland) | volume = 13 | issue = | pages = 467–474 | date = 2018 | pmid = 30426084 | pmc = 6227735 | doi = 10.1515/med-2018-0062 }}{{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 = 302–9 | date = February 2005 | pmid = 15715976 | doi = 10.1016/j.micinf.2004.12.006 | url = }} Individuals homozygous for this mutation (Δ32/Δ32) lack functional CCR5 on cell surfaces and exhibit strong resistance to HIV-1 infection, while heterozygotes (Δ32/+) show delayed disease progression and reduced viral loads. The allele occurs in approximately 1% of Caucasians, with higher frequencies in Northern Europe, suggesting historical selective pressures such as infectious diseases. Despite its protective role against HIV, CCR5-Δ32 homozygosity may increase susceptibility to flaviviruses like West Nile virus and tick-borne encephalitis due to impaired immune responses.{{cite journal | vauthors = Lopalco L | title = CCR5: From Natural Resistance to a New Anti-HIV Strategy | journal = Viruses | volume = 2 | issue = 2 | pages = 574–600 | date = February 2010 | pmid = 21994649 | pmc = 3185609 | doi = 10.3390/v2020574 | doi-access = free | url = }} This mutation has also influenced therapeutic strategies, including gene-editing approaches aimed at mimicking its HIV-resistant phenotype.{{cite journal | vauthors = Mohamed H, Gurrola T, Berman R, Collins M, Sariyer IK, Nonnemacher MR, Wigdahl B | title = Targeting CCR5 as a Component of an HIV-1 Therapeutic Strategy | journal = Frontiers in Immunology | volume = 12 | issue = | pages = 816515 | date = 2021 | pmid = 35126374 | pmc = 8811197 | doi = 10.3389/fimmu.2021.816515 | doi-access = free }}

{{further|Long-term nonprogressor}}

• Discovery and development of CCR5 receptor antagonists
• Entry inhibitor
• HIV tropism
• Stephen Crohn
• HIV immunity

{{Reflist}}

{{refbegin|32em}}

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{{refend}}

• [https://www.pbs.org/wgbh/evolution/library/10/4/l_104_06.html Video and text from a PBS documentary about the discovery of CCR5]
• {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2228 | title = Chemokine Receptors: CCR5 | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | access-date = 21 July 2006 | archive-date = 18 January 2021 | archive-url = https://web.archive.org/web/20210118033248/https://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2228 | url-status = dead }}
• [http://crdd.osdd.net/raghava/hivcopred/ HIVcoPred] A server for prediction of HIV coreceptor usage (CCR5). [http://dx.plos.org/10.1371/journal.pone.0061437 PLoS ONE 8(4): e61437]
• {{UCSC gene info|CCR5}}
• {{PDBe-KB2|P51681|C-C chemokine receptor type 5}}

{{AIDS}}

{{Chemokine receptors}}

{{Clusters of differentiation}}

{{Chemokine receptor modulators}}

Category:Clusters of differentiation

Category:Genes on human chromosome 3

Category:Chemokine receptors

Category:T cells