Novel alleles of the chemokine-receptor gene CCR5 (original) (raw)

Abstract

The CCR5 gene encodes a cell-surface chemokine-receptor molecule that serves as a coreceptor for macrophage-tropic strains of HIV-1. Mutations in this gene may alter expression or function of the protein product, thereby altering chemokine binding/signaling or HIV-1 infection of cells that normally express CCR5 protein. Indeed, homozygotes for a 32-bp deletion allele of CCR5 (CCR5-delta 32), which causes a frameshift at amino acid 185, are relatively resistant to HIV-1 infection. Here we report the identification of 16 additional mutations in the coding region of the CCR5 gene, all but 3 of which are codon altering or "nonsynonymous." Most mutations were rare (found only once or twice in the sample); five were detected exclusively among African Americans, whereas eight were observed only in Caucasians. The mutations included 11 codon-altering nonsynonymous variants, one trinucleotide deletion, one chain-termination mutant, and three synonymous mutations. The high predominance of codon-altering alleles among CCR5 mutants (14/17 [81%], including CCR5-delta 32) is consistent with an adaptive accumulation of function-altering alleles for this gene, perhaps as a consequence of historic selective pressures.

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Selected References

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  1. 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]
  2. Ansari-Lari M. A., Liu X. M., Metzker M. L., Rut A. R., Gibbs R. A. The extent of genetic variation in the CCR5 gene. Nat Genet. 1997 Jul;16(3):221–222. doi: 10.1038/ng0797-221. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. 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]
  5. 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]
  6. Combadiere C., Ahuja S. K., Tiffany H. L., Murphy P. M. Cloning and functional expression of CC CKR5, a human monocyte CC chemokine receptor selective for MIP-1(alpha), MIP-1(beta), and RANTES. J Leukoc Biol. 1996 Jul;60(1):147–152. doi: 10.1002/jlb.60.1.147. [DOI] [PubMed] [Google Scholar]
  7. Connor R. I., Ho D. D. Human immunodeficiency virus type 1 variants with increased replicative capacity develop during the asymptomatic stage before disease progression. J Virol. 1994 Jul;68(7):4400–4408. doi: 10.1128/jvi.68.7.4400-4408.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cullen M., Noble J., Erlich H., Thorpe K., Beck S., Klitz W., Trowsdale J., Carrington M. Characterization of recombination in the HLA class II region. Am J Hum Genet. 1997 Feb;60(2):397–407. [PMC free article] [PubMed] [Google Scholar]
  9. 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]
  10. 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]
  11. 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]
  12. 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]
  13. 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]
  14. 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]
  15. 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]
  16. 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]
  17. 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]
  18. 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]
  19. Premack B. A., Schall T. J. Chemokine receptors: gateways to inflammation and infection. Nat Med. 1996 Nov;2(11):1174–1178. doi: 10.1038/nm1196-1174. [DOI] [PubMed] [Google Scholar]
  20. Roos M. T., Lange J. M., de Goede R. E., Coutinho R. A., Schellekens P. T., Miedema F., Tersmette M. Viral phenotype and immune response in primary human immunodeficiency virus type 1 infection. J Infect Dis. 1992 Mar;165(3):427–432. doi: 10.1093/infdis/165.3.427. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. 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]
  23. 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]
  24. Schuitemaker H., Koot M., Kootstra N. A., Dercksen M. W., de Goede R. E., van Steenwijk R. P., Lange J. M., Schattenkerk J. K., Miedema F., Tersmette M. Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus population. J Virol. 1992 Mar;66(3):1354–1360. doi: 10.1128/jvi.66.3.1354-1360.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Smith M. W., Dean M., Carrington M., Winkler C., Huttley G. A., Lomb D. A., Goedert J. J., O'Brien T. R., Jacobson L. P., Kaslow R. Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study. Science. 1997 Aug 15;277(5328):959–965. doi: 10.1126/science.277.5328.959. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. 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]