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Regulatory polymorphisms in the cyclophilin A gene, PPIA, accelerate progression to AIDS

  1. Author:
    An, P.
    Wang, L. H.
    Hutcheson-Dilks, H.
    Nelson, G.
    Donfield, S.
    Goedert, J. J.
    Rinaldo, C. R.
    Buchbinder, S.
    Kirk, G. D.
    O'Brien, S. J.
    Winkler, C. A.

  2. Author Address

    Natl Canc Frederick, Sci Applicat Int Corp, Lab Genom Divers, Frederick, MD USA. Natl Canc Inct, Lab Genome Divers, Frederick, MD USA. Rho Inc, Chapel Hill, NC USA. NCI, Div Canc, Vira Epidemiol Branch, Bethesda, MD USA. Univ Pittsburgh, Dept Infect Dis & Microbiol, Grad Sch Publ Hlth, Pittsburgh, PA 15260 USA. San Francisco, Dept Publ Hlth, San Francisco, CA USA. Johns Hopkins Univ, Dept Epidemiol, Sch Publ Hlth, Baltimore, MD 21218 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA.;Winkler, CA, NCI, Sci Applicat Int Corp, Lab Genom Divers, Frederick, MD 21701 USA.;winkler@mail.ncifcrf.gov
    1. Year: 2007
    2. Date: Jun
  2. Journal: Plos Pathogens
    1. 3
    2. 6
    3. Pages: 849-857
  4. Type of Article: Article
  5. Article Number: e88
  6. ISSN: 1553-7366
  1. Abstract:

    Human cyclophilin A, or CypA, encoded by the gene peptidyl prolyl isomerase A (PPIA), is incorporated into the HIV type 1 (HIV-1) virion and promotes HIV-1 infectivity by facilitating virus uncoating. We examined the effect of single nucleotide polymorphisms (SNPs) and haplotypes within the PPIA gene on HIV-1 infection and disease progression in five HIV-1 longitudinal history cohorts. Kaplan- Meier survival statistics and Cox proportional hazards model were used to assess time to AIDS outcomes. Among eight SNPs tested, two promoter SNPs (SNP3 and SNP4) in perfect linkage disequilibrium were associated with more rapid CD4(+) T- cell loss (relative hazard = 3.7, p = 0.003) in African Americans. Among European Americans, these alleles were also associated with a significant trend to more rapid progression to AIDS in a multi-point categorical analysis (p = 0.005). Both SNPs showed differential nuclear protein- binding efficiencies in a gel shift assay. In addition, one SNP (SNP5) located in the 5 ' UTR previously shown to be associated with higher ex vivo HIV-1 replication was found to be more frequent in HIV-1-positive individuals than in those highly exposed uninfected individuals. These results implicate regulatory PPIA polymorphisms as a component of genetic susceptibility to HIV-1 infection or disease progression, affirming the important role of PPIA in HIV-1 pathogenesis.

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External Sources

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  2. DOI: 10.1371/journal.ppat.0030088
  3. View record in Web of Science®
  4. WOS: 000248511400015

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