Abstract
Since the late 1970s, 8.4 million people worldwide, including 1.7 million children, have died of AIDS, and an estimated 22 million people are infected with human immunodeficiency virus (HIV)(1). During 1995 and 1996, major clinical and laboratory discoveries regarding HIV pathogenesis provided new hope for the prevention and treatment of HIV infection. One major discovery was that members of the chemokine receptor family serve as cofactors for HIV entry into cells. We describe the role of allelic polymorphism in the gene coding for the CCR5 chemokine receptor with regard to susceptibility to and disease course of HIV infection. We also examine the effect of this discovery on medical and public health practices.
Full Text
The Full Text of this article is available as a PDF (229.1 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Alkhatib G., Combadiere C., Broder C. C., Feng Y., Kennedy P. E., Murphy P. M., Berger E. A. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science. 1996 Jun 28;272(5270):1955–1958. doi: 10.1126/science.272.5270.1955. [DOI] [PubMed] [Google Scholar]
- Atchison R. E., Gosling J., Monteclaro F. S., Franci C., Digilio L., Charo I. F., Goldsmith M. A. Multiple extracellular elements of CCR5 and HIV-1 entry: dissociation from response to chemokines. Science. 1996 Dec 13;274(5294):1924–1926. doi: 10.1126/science.274.5294.1924. [DOI] [PubMed] [Google Scholar]
- Biti R., Ffrench R., Young J., Bennetts B., Stewart G., Liang T. HIV-1 infection in an individual homozygous for the CCR5 deletion allele. Nat Med. 1997 Mar;3(3):252–253. doi: 10.1038/nm0397-252. [DOI] [PubMed] [Google Scholar]
- Bleul C. C., Wu L., Hoxie J. A., Springer T. A., Mackay C. R. The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes. Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1925–1930. doi: 10.1073/pnas.94.5.1925. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brinkman B. M., Keet I. P., Miedema F., Verweij C. L., Klein M. R. Polymorphisms within the human tumor necrosis factor-alpha promoter region in human immunodeficiency virus type 1-seropositive persons. J Infect Dis. 1997 Jan;175(1):188–190. doi: 10.1093/infdis/175.1.188. [DOI] [PubMed] [Google Scholar]
- Choe H., Farzan M., Sun Y., Sullivan N., Rollins B., Ponath P. D., Wu L., Mackay C. R., LaRosa G., Newman W. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell. 1996 Jun 28;85(7):1135–1148. doi: 10.1016/s0092-8674(00)81313-6. [DOI] [PubMed] [Google Scholar]
- Cocchi F., DeVico A. L., Garzino-Demo A., Arya S. K., Gallo R. C., Lusso P. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science. 1995 Dec 15;270(5243):1811–1815. doi: 10.1126/science.270.5243.1811. [DOI] [PubMed] [Google Scholar]
- Cocchi F., DeVico A. L., Garzino-Demo A., Cara A., Gallo R. C., Lusso P. The V3 domain of the HIV-1 gp120 envelope glycoprotein is critical for chemokine-mediated blockade of infection. Nat Med. 1996 Nov;2(11):1244–1247. doi: 10.1038/nm1196-1244. [DOI] [PubMed] [Google Scholar]
- Combadiere C., Ahuja S. K., Murphy P. M. Cloning and functional expression of a human eosinophil CC chemokine receptor. J Biol Chem. 1996 May 3;271(18):11034–11034. [PubMed] [Google Scholar]
- D'Souza M. P., Harden V. A. Chemokines and HIV-1 second receptors. Confluence of two fields generates optimism in AIDS research. Nat Med. 1996 Dec;2(12):1293–1300. doi: 10.1038/nm1296-1293. [DOI] [PubMed] [Google Scholar]
- Daugherty B. L., Siciliano S. J., DeMartino J. A., Malkowitz L., Sirotina A., Springer M. S. Cloning, expression, and characterization of the human eosinophil eotaxin receptor. J Exp Med. 1996 May 1;183(5):2349–2354. doi: 10.1084/jem.183.5.2349. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dean M., Carrington M., Winkler C., Huttley G. A., Smith M. W., Allikmets R., Goedert J. J., Buchbinder S. P., Vittinghoff E., Gomperts E. 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. Science. 1996 Sep 27;273(5283):1856–1862. doi: 10.1126/science.273.5283.1856. [DOI] [PubMed] [Google Scholar]
- Deng H., Liu R., Ellmeier W., Choe S., Unutmaz D., Burkhart M., Di Marzio P., Marmon S., Sutton R. E., Hill C. M. Identification of a major co-receptor for primary isolates of HIV-1. Nature. 1996 Jun 20;381(6584):661–666. doi: 10.1038/381661a0. [DOI] [PubMed] [Google Scholar]
- Doranz B. J., Rucker J., Yi Y., Smyth R. J., Samson M., Peiper S. C., Parmentier M., Collman R. G., Doms R. W. A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell. 1996 Jun 28;85(7):1149–1158. doi: 10.1016/s0092-8674(00)81314-8. [DOI] [PubMed] [Google Scholar]
- Dragic T., Litwin V., Allaway G. P., Martin S. R., Huang Y., Nagashima K. A., Cayanan C., Maddon P. J., Koup R. A., Moore J. P. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature. 1996 Jun 20;381(6584):667–673. doi: 10.1038/381667a0. [DOI] [PubMed] [Google Scholar]
- Easterbrook P. J., Chmiel J. S., Hoover D. R., Saah A. J., Kaslow R. A., Kingsley L. A., Detels R. Racial and ethnic differences in human immunodeficiency virus type 1 (HIV-1) seroprevalence among homosexual and bisexual men. The Multicenter AIDS Cohort Study. Am J Epidemiol. 1993 Sep 15;138(6):415–429. doi: 10.1093/oxfordjournals.aje.a116874. [DOI] [PubMed] [Google Scholar]
- Eugen-Olsen J., Iversen A. K., Garred P., Koppelhus U., Pedersen C., Benfield T. L., Sorensen A. M., Katzenstein T., Dickmeiss E., Gerstoft J. Heterozygosity for a deletion in the CKR-5 gene leads to prolonged AIDS-free survival and slower CD4 T-cell decline in a cohort of HIV-seropositive individuals. AIDS. 1997 Mar;11(3):305–310. doi: 10.1097/00002030-199703110-00007. [DOI] [PubMed] [Google Scholar]
- Feng Y., Broder C. C., Kennedy P. E., Berger E. A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996 May 10;272(5263):872–877. doi: 10.1126/science.272.5263.872. [DOI] [PubMed] [Google Scholar]
- Fowke K. R., Nagelkerke N. J., Kimani J., Simonsen J. N., Anzala A. O., Bwayo J. J., MacDonald K. S., Ngugi E. N., Plummer F. A. Resistance to HIV-1 infection among persistently seronegative prostitutes in Nairobi, Kenya. Lancet. 1996 Nov 16;348(9038):1347–1351. doi: 10.1016/S0140-6736(95)12269-2. [DOI] [PubMed] [Google Scholar]
- Garred P., Eugen-Olsen J., Iversen A. K., Benfield T. L., Svejgaard A., Hofmann B. Dual effect of CCR5 delta 32 gene deletion in HIV-1-infected patients. Copenhagen AIDS Study Group. Lancet. 1997 Jun 28;349(9069):1884–1884. doi: 10.1016/s0140-6736(05)63874-3. [DOI] [PubMed] [Google Scholar]
- Garred P., Madsen H. O., Balslev U., Hofmann B., Pedersen C., Gerstoft J., Svejgaard A. Susceptibility to HIV infection and progression of AIDS in relation to variant alleles of mannose-binding lectin. Lancet. 1997 Jan 25;349(9047):236–240. doi: 10.1016/S0140-6736(96)08440-1. [DOI] [PubMed] [Google Scholar]
- He J., Chen Y., Farzan M., Choe H., Ohagen A., Gartner S., Busciglio J., Yang X., Hofmann W., Newman W. CCR3 and CCR5 are co-receptors for HIV-1 infection of microglia. Nature. 1997 Feb 13;385(6617):645–649. doi: 10.1038/385645a0. [DOI] [PubMed] [Google Scholar]
- Hill A. V. HIV and HLA: confusion or complexity? Nat Med. 1996 Apr;2(4):395–396. doi: 10.1038/nm0496-395. [DOI] [PubMed] [Google Scholar]
- Huang Y., Paxton W. A., Wolinsky S. M., Neumann A. U., Zhang L., He T., Kang S., Ceradini D., Jin Z., Yazdanbakhsh K. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat Med. 1996 Nov;2(11):1240–1243. doi: 10.1038/nm1196-1240. [DOI] [PubMed] [Google Scholar]
- Kaslow R. A., Carrington M., Apple R., Park L., Muñoz A., Saah A. J., Goedert J. J., Winkler C., O'Brien S. J., Rinaldo C. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat Med. 1996 Apr;2(4):405–411. doi: 10.1038/nm0496-405. [DOI] [PubMed] [Google Scholar]
- Khoo S. H., Pepper L., Snowden N., Hajeer A. H., Vallely P., Wilkins E. G., Mandal B. K., Ollier W. E. Tumour necrosis factor c2 microsatellite allele is associated with the rate of HIV disease progression. AIDS. 1997 Mar 15;11(4):423–428. doi: 10.1097/00002030-199704000-00004. [DOI] [PubMed] [Google Scholar]
- Lapham C. K., Ouyang J., Chandrasekhar B., Nguyen N. Y., Dimitrov D. S., Golding H. Evidence for cell-surface association between fusin and the CD4-gp120 complex in human cell lines. Science. 1996 Oct 25;274(5287):602–605. doi: 10.1126/science.274.5287.602. [DOI] [PubMed] [Google Scholar]
- Liu R., Paxton W. A., Choe S., Ceradini D., Martin S. R., Horuk R., MacDonald M. E., Stuhlmann H., Koup R. A., Landau N. R. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell. 1996 Aug 9;86(3):367–377. doi: 10.1016/s0092-8674(00)80110-5. [DOI] [PubMed] [Google Scholar]
- Malkovsky M. HLA and natural history of HIV infection. Lancet. 1996 Jul 20;348(9021):142–143. doi: 10.1016/s0140-6736(05)66106-5. [DOI] [PubMed] [Google Scholar]
- Martinson J. J., Chapman N. H., Rees D. C., Liu Y. T., Clegg J. B. Global distribution of the CCR5 gene 32-basepair deletion. Nat Genet. 1997 May;16(1):100–103. doi: 10.1038/ng0597-100. [DOI] [PubMed] [Google Scholar]
- McNeil A. J., Yap P. L., Gore S. M., Brettle R. P., McColl M., Wyld R., Davidson S., Weightman R., Richardson A. M., Robertson J. R. Association of HLA types A1-B8-DR3 and B27 with rapid and slow progression of HIV disease. QJM. 1996 Mar;89(3):177–185. doi: 10.1093/qjmed/89.3.177. [DOI] [PubMed] [Google Scholar]
- Michael N. L., Chang G., Louie L. G., Mascola J. R., Dondero D., Birx D. L., Sheppard H. W. The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression. Nat Med. 1997 Mar;3(3):338–340. doi: 10.1038/nm0397-338. [DOI] [PubMed] [Google Scholar]
- Miller L. H. Impact of malaria on genetic polymorphism and genetic diseases in Africans and African Americans. Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2415–2419. doi: 10.1073/pnas.91.7.2415. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Murphy P. M. Chemokine receptors: structure, function and role in microbial pathogenesis. Cytokine Growth Factor Rev. 1996 Jun;7(1):47–64. doi: 10.1016/1359-6101(96)00009-3. [DOI] [PubMed] [Google Scholar]
- Napolitano M., Zingoni A., Bernardini G., Spinetti G., Nista A., Storlazzi C. T., Rocchi M., Santoni A. Molecular cloning of TER1, a chemokine receptor-like gene expressed by lymphoid tissues. J Immunol. 1996 Oct 1;157(7):2759–2763. [PubMed] [Google Scholar]
- O'Brien T. R., Winkler C., Dean M., Nelson J. A., Carrington M., Michael N. L., White G. C., 2nd HIV-1 infection in a man homozygous for CCR5 delta 32. Lancet. 1997 Apr 26;349(9060):1219–1219. doi: 10.1016/s0140-6736(97)24017-1. [DOI] [PubMed] [Google Scholar]
- Oravecz T., Pall M., Norcross M. A. Beta-chemokine inhibition of monocytotropic HIV-1 infection. Interference with a postbinding fusion step. J Immunol. 1996 Aug 15;157(4):1329–1332. [PubMed] [Google Scholar]
- Paxton W. A., Dragic T., Koup R. A., Moore J. P. The beta-chemokines, HIV type 1 second receptors, and exposed uninfected persons. AIDS Res Hum Retroviruses. 1996 Sep 1;12(13):1203–1207. doi: 10.1089/aid.1996.12.1203. [DOI] [PubMed] [Google Scholar]
- Paxton W. A., Martin S. R., Tse D., O'Brien T. R., Skurnick J., VanDevanter N. L., Padian N., Braun J. F., Kotler D. P., Wolinsky S. M. Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who remain uninfected despite multiple high-risk sexual exposure. Nat Med. 1996 Apr;2(4):412–417. doi: 10.1038/nm0496-412. [DOI] [PubMed] [Google Scholar]
- Pleskoff O., Tréboute C., Brelot A., Heveker N., Seman M., Alizon M. Identification of a chemokine receptor encoded by human cytomegalovirus as a cofactor for HIV-1 entry. Science. 1997 Jun 20;276(5320):1874–1878. doi: 10.1126/science.276.5320.1874. [DOI] [PubMed] [Google Scholar]
- Ponath P. D., Qin S., Post T. W., Wang J., Wu L., Gerard N. P., Newman W., Gerard C., Mackay C. R. Molecular cloning and characterization of a human eotaxin receptor expressed selectively on eosinophils. J Exp Med. 1996 Jun 1;183(6):2437–2448. doi: 10.1084/jem.183.6.2437. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rowland-Jones S. L., McMichael A. Immune responses in HIV-exposed seronegatives: have they repelled the virus? Curr Opin Immunol. 1995 Aug;7(4):448–455. doi: 10.1016/0952-7915(95)80087-5. [DOI] [PubMed] [Google Scholar]
- Rowland-Jones S., Sutton J., Ariyoshi K., Dong T., Gotch F., McAdam S., Whitby D., Sabally S., Gallimore A., Corrah T. HIV-specific cytotoxic T-cells in HIV-exposed but uninfected Gambian women. Nat Med. 1995 Jan;1(1):59–64. doi: 10.1038/nm0195-59. [DOI] [PubMed] [Google Scholar]
- Rucker J., Samson M., Doranz B. J., Libert F., Berson J. F., Yi Y., Smyth R. J., Collman R. G., Broder C. C., Vassart G. Regions in beta-chemokine receptors CCR5 and CCR2b that determine HIV-1 cofactor specificity. Cell. 1996 Nov 1;87(3):437–446. doi: 10.1016/s0092-8674(00)81364-1. [DOI] [PubMed] [Google Scholar]
- Samson M., Labbe O., Mollereau C., Vassart G., Parmentier M. Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry. 1996 Mar 19;35(11):3362–3367. doi: 10.1021/bi952950g. [DOI] [PubMed] [Google Scholar]
- Samson M., Libert F., Doranz B. J., Rucker J., Liesnard C., Farber C. M., Saragosti S., Lapoumeroulie C., Cognaux J., Forceille C. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature. 1996 Aug 22;382(6593):722–725. doi: 10.1038/382722a0. [DOI] [PubMed] [Google Scholar]
- Simmons G., Wilkinson D., Reeves J. D., Dittmar M. T., Beddows S., Weber J., Carnegie G., Desselberger U., Gray P. W., Weiss R. A. Primary, syncytium-inducing human immunodeficiency virus type 1 isolates are dual-tropic and most can use either Lestr or CCR5 as coreceptors for virus entry. J Virol. 1996 Dec;70(12):8355–8360. doi: 10.1128/jvi.70.12.8355-8360.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Soto-Ramirez L. E., Renjifo B., McLane M. F., Marlink R., O'Hara C., Sutthent R., Wasi C., Vithayasai P., Vithayasai V., Apichartpiyakul C. HIV-1 Langerhans' cell tropism associated with heterosexual transmission of HIV. Science. 1996 Mar 1;271(5253):1291–1293. doi: 10.1126/science.271.5253.1291. [DOI] [PubMed] [Google Scholar]
- Steel C. M., Ludlam C. A., Beatson D., Peutherer J. F., Cuthbert R. J., Simmonds P., Morrison H., Jones M. HLA haplotype A1 B8 DR3 as a risk factor for HIV-related disease. Lancet. 1988 May 28;1(8596):1185–1188. doi: 10.1016/s0140-6736(88)92009-0. [DOI] [PubMed] [Google Scholar]
- Theodorou I., Meyer L., Magierowska M., Katlama C., Rouzioux C. HIV-1 infection in an individual homozygous for CCR5 delta 32. Seroco Study Group. Lancet. 1997 Apr 26;349(9060):1219–1220. [PubMed] [Google Scholar]
- Tournamille C., Colin Y., Cartron J. P., Le Van Kim C. Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals. Nat Genet. 1995 Jun;10(2):224–228. doi: 10.1038/ng0695-224. [DOI] [PubMed] [Google Scholar]
- Trkola A., Dragic T., Arthos J., Binley J. M., Olson W. C., Allaway G. P., Cheng-Mayer C., Robinson J., Maddon P. J., Moore J. P. CD4-dependent, antibody-sensitive interactions between HIV-1 and its co-receptor CCR-5. Nature. 1996 Nov 14;384(6605):184–187. doi: 10.1038/384184a0. [DOI] [PubMed] [Google Scholar]
- Wain-Hobson S. HIV. One on one meets two. Nature. 1996 Nov 14;384(6605):117–118. doi: 10.1038/384117a0. [DOI] [PubMed] [Google Scholar]
- Wu L., Gerard N. P., Wyatt R., Choe H., Parolin C., Ruffing N., Borsetti A., Cardoso A. A., Desjardin E., Newman W. CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature. 1996 Nov 14;384(6605):179–183. doi: 10.1038/384179a0. [DOI] [PubMed] [Google Scholar]
- Wu L., Paxton W. A., Kassam N., Ruffing N., Rottman J. B., Sullivan N., Choe H., Sodroski J., Newman W., Koup R. A. CCR5 levels and expression pattern correlate with infectability by macrophage-tropic HIV-1, in vitro. J Exp Med. 1997 May 5;185(9):1681–1691. doi: 10.1084/jem.185.9.1681. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhang L., Huang Y., He T., Cao Y., Ho D. D. HIV-1 subtype and second-receptor use. Nature. 1996 Oct 31;383(6603):768–768. doi: 10.1038/383768a0. [DOI] [PubMed] [Google Scholar]
- Zimmerman P. A., Buckler-White A., Alkhatib G., Spalding T., Kubofcik J., Combadiere C., Weissman D., Cohen O., Rubbert A., Lam G. Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk. Mol Med. 1997 Jan;3(1):23–36. [PMC free article] [PubMed] [Google Scholar]
