Abstract
Viral and host factors influence the rate of HIV-1 disease progression1. For HIV-1 to fuse, a CD4+ cell must express a co-receptor that the virus can use2,3. The chemokine receptors CCR5 and CXCR4 are used by R5 and X4 viruses, respectively4. Most new infections involve transmission of R5 viruses, but variants can arise later that also use CXCR4 (R5-X4 or X4 viruses)2–6. This is associated with an increased rate of CD4+ T-cell loss and poor prognosis2–6. The ability of host cells to support HIV-1 entry also influences progression. The absence of CCR5 in approximately 1% of the Caucasian population, due to homozygosity for a 32-nucleotide deletion in the coding region (Δ32-CCR5 allele), very strongly protects against HIV-1 transmission7–10. Heterozygosity for the Δ32-CCR5 allele delays progression typically by 2 years9,10. A recent study showed that a conservative substitution (V64I) in the coding region of CCR2 also has a significant impact on disease progression, but not on HIV-1 transmission11. This was unexpected, since CCR2 is rarely used as a co-receptor in vitro2,3 and the V64I change is in a trans-membrane region11. Because a subsequent study did not confirm this effect on progression to disease12, we analyzed CCR2-V64I using subjects in the Chicago MACS. We show that CCR2-V64I is indeed protective against disease progression and go on to show that the CCR2-V64I allele is in complete linkage disequilibrium with a point mutation in the CCR5 regulatory region.
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 Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Fauci, A.S. Host factors and the pathogenesis of HIV-induced disease. Nature 384, 529–534 (1996).
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 (suppl A), S3–S16 (1997).
Berger, E.A. et al. HIV-1 phenotype classified by co-receptor usage. Nature 391, 240 (1998).
Zhu, T. et al. Genotypic and phenotypic characterization of HIV-1 patients with primary infection. Science 261, 1179–1181 (1993).
Richman, D.D. & Bozzette, S.A. The impact of the syncytium-inducing phenotype of human immunodeficiency virus on disease progression. J. Inf. Dis. 169, 968–974 (1994).
Liu, R. et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86, 367–378 (1996).
Samson, M. et al. Resistance to HIV-1 infection of Caucasian individuals bearing mutant alleles of the CKR5 chemokine receptor gene. Nature 82, 722–725 (1996).
Dean, M. et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion of the CKR5 structural allele. Science 273,1856–1862 (1996).
Huang, Y. et al. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nature Med. 2,1240–1243 (1996).
Smith, M.W. et al. Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Science 277, 959–965 (1997).
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).
Kostrikis, L.G., Tyagi, S., Mhlanga, M.M., Ho, D.D. & Kramer, F.R. Spectral genotyping of human alleles. Science (in the press).
Smith, M.W. et al. CCR2 chemokine receptor and AIDS progression. Nature Med. 3, 1052–1053 (1997).
Mummidi, S., Ahuja, S.S., McDaniel, B. & 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).
Tyagi, S. & Kramer, F. Molecular beacons: probe that fluorescence upon hybridization. Nature Biotech. 14, 471–476 (1996).
Premack, B.A. & Schall, T.J. Chemokine receptors: gateways to inflammation and infection. Nature Med. 2, 1174–1178 (1996).
Paxton, W.A. et al. Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who remain uninfected despite multiple high-risk sexual exposures. Nature Med. 2, 412–417 (1996).
Wu, L. et al. CCR5 levels and expression pattern correlate with infectability by macrophage-tropic HIV-1, in vitro. J. Exp. Med. 185, 1681–1691 (1997).
Trkola, A. et al. CD4-dependent, antibody-sensitive interactions between HIV-1 and its co-receptor CCR5. Nature 384, 184–186 (1996).
Moore, J.P., Implications for HIV pathogenesis and therapy. Science 276, 51–52 (1997).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kostrikis, L., Huang, Y., Moore, J. et al. A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation. Nat Med 4, 350–353 (1998). https://doi.org/10.1038/nm0398-350
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nm0398-350
This article is cited by
-
New genetic and epigenetic insights into the chemokine system: the latest discoveries aiding progression toward precision medicine
Cellular & Molecular Immunology (2023)
-
Non-viral Gene Disruption by CRISPR/Cas9 Delivery Using Cell-permeable and Protein-stabilizing 30Kc19 Protein
Biotechnology and Bioprocess Engineering (2020)
-
Transcriptome Sequencing of Peripheral Blood Mononuclear Cells from Elite Controller-Long Term Non Progressors
Scientific Reports (2019)
-
Dual CCR5/CCR2 targeting: opportunities for the cure of complex disorders
Cellular and Molecular Life Sciences (2019)
-
CCR2-V64I genetic polymorphism: a possible involvement in HER2+ breast cancer
Clinical and Experimental Medicine (2016)