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MCP-1-MCP-3-eotaxin gene cluster influences HIV-1 transmission

  1. Author:
    Modi, W. S.
    Goedert, J. J.
    Strathdee, S.
    Buchbinder, S.
    Detels, R.
    Donfield, S.
    O'Brien, S. J.
    Winkler, C.

  2. Author Address

    Winkler, C, NCI, SAIC Frederick, Frederick, MD 21702 USA NCI, SAIC Frederick, Frederick, MD 21702 USA. NCI, Lab Genom Divers, Frederick, MD 21702 USA. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. Dept Publ Hlth, San Francisco, CA USA. Rho Inc, Chapel Hill, NC USA.
    1. Year: 2003
  2. Journal: Aids
    1. 17
    2. 16
    3. Pages: 2357-2365
  4. Type of Article: Article
  1. Abstract:

    Background: MCP-1 (CCL2), MCP-3 (CCL 7), and eotaxin (CCL 17) are genes for CC chemokines clustered on the long arm of chromosome 17. Previous studies have implicated these chemokines in monocyte recruitment, viral replication, and anti-HIV cytotoxic T cell responses. An epidemiological analysis identified genetic variants influencing HIV-1 transmission and disease progression.Methods: Genomic DNA from over 3000 participants enrolled in five natural history cohorts in the United States were analyzed. Nine single nucleotide polymorphisms (SNP) covering 33 kb containing these three genes were genotyped using the polymerase chain reaction. Distortions in allele, genotype, and haplotype frequencies were assessed with respect to HIV-1 transmission and rates of disease progression using categorical and survival analyses.Results: Extensive linkage disequilibrium was observed. Three SNP (-2136T located in the MCP-1 promoter region, 767G in intron 1 of MCP-1, and -1385A in the Eotaxin promoter) were nearly always found together on a 31 kb haplotype (H7) containing the three genes. Frequencies of the three variants and the H7 haplotype were significantly elevated (odds ratio, 0.6; P = 0.005-0.01) in uninfected European-Americans repeatedly exposed to HIV-1 through high-risk sexual behavior or contaminated blood products.Conclusions: Although the extensive linkage disequilibrium precludes positive identification of the causal variant, the results suggest that genetic variation in the H7 region influences susceptibility to HIV-1 infection. Since these chemokines do not bind the primary HIV-1 coreceptors CCR5 or CXCR4, the observed influence on transmission may result from activation of the immune system in response to infection rather than receptor blockage. (C) 2003 Lippincott Williams Wilkins

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