Allelic variants for the HIV-1 co-receptors chemokine receptor 5 (CCR5) and CCR2, as well as the ligand for the co-receptor CXCR4, stromal-derived factor (SDF-1), have been associated with a delay in disease progression. We began this study to test whether polymorphisms in the CCRS regulatory regions influence the course of HIV-1 disease, as well as to examine the role of the previously identified allelic variants in 1,090 HIV-1 infected individuals. Here we describe the evolutionary relationships between the phenotypically important CCRS alleles, define precisely the CCR5 regulatory sequences that are linked to the CCR5-Δ32 and CCR2-64I polymorphisms, and identify genotypes associated with altered rates of HIV-1 disease progression. The disease-retarding effects of the CCR2-64I allele were found in African Americans but not in Caucasians, and the SDF1-3′A/3′A genotype was associated with an accelerated progression to death. In contrast, the CCR5-Δ32 allele and a CCR5 promoter mutation with which it is tightly linked were associated with limited disease-retarding effects. Collectively, these findings draw attention to a complex array of genetic determinants in the HIV-host interplay.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
References
Moore, J.P., Trkola, A. & Dragic, T. Co-receptors for HIV-1 entry. Curr. Opin. Immunol. 9, 551–562 (1997).
Berger, E.A. HIV entry and tropism: the chemokine receptor connection. AIDS 11, S316 (1997).
Alkhatib, C. et al. CC CKR5: a RANTES, MIP-1 alpha, MIP-1 beta receptor as a fusion cofactor for macrophagetropic HIV-1. Science 272, 1955–1958 (1996).
Deng, H. et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature 381, 661–666 (1996).
Dragic, T. et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC- CKR-5. Nature 381, 667–673 (1996).
Doranz, B.J. et al. 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 85, 1149–1158 (1996).
Feng, Y., Border, C.C., Kennedy, P.E. & Berger, E.A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272, 872–877 (1996).
Bleul, C.C. et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 382, 829–833 (1996).
Oberlin, E. et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 382, 833–835 (1996).
Liu, R. et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86, 367–377 (1996).
Samson, M. et al. Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382, 722–725 (1996).
Dean, M. et al. 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 273, 1856–1862 (1996).
Moore, J.P. Coreceptors: implications for HIV pathogenesis and therapy. Science 276, 51–52 (1997).
Wu, L. et al. CCR5 levels and expression pattern correlate with infectability by macrophagetropic HIV-1, in vitro. J. Exp. Med. 185, 1681–1691 (1997).
Berger, E.A. et al. A new classification for HIV-1. Nature 391, 240 (1998).
Mummidi, S., Ahuja, S.S., McDaniel, B.L. & Ahuja, S.K., The human CC chemokine receptor 5 (CCR5) gene. Multiple transcripts with 5′-end heterogeneity, dual promoter usage, and evidence for polymorphisms within the regulatory regions and noncoding exons. J. Biol. Chem. 272, 30662–30671 (1997).
Zimmerman, P.A. et al. 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. 3, 23–36 (1997).
de Roda Husman, A.M. et al. Association between CCR5 genotype and the clinical course of HIV-1 infection. Ann. Intern. Med. 127, 882–890 (1997).
Michael, N.L. et al. The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression. Nature Med. 3, 338–340 (1997).
Meyer, L. et al. Early protective effect of CCR-5 delta 32 heterozygosity on HIV-1 disease progression: relationship with viral load. The SEROCO Study Group. AIDS 11, F7378 (1997).
Katzenstein, T.L. et al. HIV-infected individuals with the CCR delta32/CCR5 genotype have lower HIV RNA levels and higher CD4 cell counts in the early years of the infection than do patients with the wild type. Copenhagen AIDS Cohort Study Group. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 16, 10–14 (1997).
Eugen-Olsen, J. et al. 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 11, 305–310 (1997).
Morawetz, R.A. et al. Genetic polymorphism of CCR5 gene and HIV disease: the heterozygous (CCR5/delta ccr5) genotype is neither essential nor sufficient for protection against disease progression. Swiss HIV Cohort. Eur. J. Immunol. 27, 3223–3227 (1997).
Huang, Y. et al. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nature Med. 2, 1240–1243 (1996).
Garred, P. Chemokine-receptor polymorphisms: clarity or confusion for HIV-1 prognosis? Lancet 351, 2–3 (1998).
Smith, M.W. et al. 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 277, 959–965 (1997).
Kostrikis, L.G. et al. A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation. Nature Med. 4, 350–353 (1998
Michael, N.L. et al. The role of CCR5 and CCR2 polymorphisms in HIV-1 transmission and disease progression. Nature Med. 3, 1160–1162 (1997).
Rizzardi, G.P. et al. CCR2 polymorphism and HIV disease. Swiss HIV Cohort. Nat Med. 4, 252–253 (1998).
Winkler, C. et al. Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. ALIVE Study, Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC). Science 279, 389–393 (1998).
Weatherall, D., Clegg, J. & Kwiatkowski, D. The role of genomics in studying genetic susceptibility to infectious disease. Genome Res. 7, 967–973 (1997).
Dawson, S.J., Morris, P.J. & Latchman, D.S. A single amino acid change converts an inhibitory transcription factor into an activator.. J. Biol. Chem. 271, 11631–11633 (1996).
Kurumbail, R.G. et al. Structural basis for selective inhibition of cyclooxygenase–2 by anti– inflammatory agents.. Nature 384, 644–648 (1996).
Swofford, D.L. PAUP: Phylogenetic analysis using parsimony, Version 3.1. Computer program distributed by the Illinois Natural History Survey, Champaign, Illinois (1993).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Mummidi, S., Ahuja, S., Gonalez, E. et al. Genealogy of the CCR5 locus and chemokine system gene variants associated with altered rates of HIV-1 disease progression. Nat Med 4, 786–793 (1998). https://doi.org/10.1038/nm0798-786
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nm0798-786