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Polymorphisms of CUL5 are associated with CD4(+) T cell loss in HIV-1 infected individuals

  1. Author:
    An, P.
    Duggal, P.
    Wang, L. H.
    O'Brien, S. J.
    Donfield, S.
    Goedert, J. J.
    Phair, J.
    Buchbinder, S.
    Kirk, G. D.
    Winkler, C. A.

  2. Author Address

    SAIC Frederick Inc, Natl Canc Inst, Lab Genom Divers, Frederick, MD USA. NHGRI, Inherited Dis Res Branch, Baltimore, MD USA. SAIC Frederick, Basic Res Program, Natl Canc Inst, Frederick, MD USA. NCI, Lab Genom Divers, Frederick, MD 21701 USA. Rho Inc, Chapel Hill, NC USA. NCI, Bethesda, MD 20892 USA. Northwestern Univ, Chicago, IL 60611 USA. San Francisco Dept Publ Hlth, San Francisco, CA USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA.;Winkler, CA, SAIC Frederick Inc, Natl Canc Inst, Lab Genom Divers, Frederick, MD USA.;winkler@mail.ncifcrf.gov
    1. Year: 2007
    2. Date: Jan
  2. Journal: Plos Genetics
    1. 3
    2. 1
  4. Type of Article: Article
  5. Article Number: e19
  6. ISSN: 1553-7390
  1. Abstract:

    Human apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (Apobec3) antiretroviral factors cause hypermutation of proviral DNA leading to degradation or replication-incompetent HIV-1. However, HIV-1 viral infectivity factor (Vif) suppresses Apobec3 activity through the Cullin 5-Elongin B-Elongin C E3 ubiquitin ligase complex. We examined the effect of genetic polymorphisms in the CUL5 gene (encoding Cullin 5 protein) on AIDS disease progression in five HIV-1 longitudinal cohorts. A total of 12 single nucleotide polymorphisms ( SNPs) spanning 93 kb in the CUL5 locus were genotyped and their haplotypes inferred. A phylogenetic network analysis revealed that CUL5 haplotypes were grouped into two clusters of evolutionarily related haplotypes. Cox survival analysis and mixed effects models were used to assess time to AIDS outcomes and CD4(+)T cell trajectories, respectively. Relative to cluster I haplotypes, the collective cluster II haplotypes were associated with more rapid CD4(+)T cell loss ( relative hazards [ RH] 1.47 and p = 0.009), in a dose-dependent fashion. This effect was mainly attributable to a single cluster II haplotype (Hap10) (RH = 2.49 and p = 0.00001), possibly due to differential nuclear protein-binding efficiencies of a Hap10-specifying SNP as indicated by a gel shift assay. Consistent effects were observed for CD4(+)T cell counts and HIV-1 viral load trajectories over time. The findings of both functional and genetic epidemiologic consequences of CUL5 polymorphism on CD4(+)T cell and HIV-1 levels point to a role for Cullin 5 in HIV-1 pathogenesis and suggest interference with the Vif-Cullin 5 pathway as a possible anti-HIV-1 therapeutic strategy.

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  2. DOI: 10.1371/journal.pgen.0030019
  3. View record in Web of Science®
  4. WOS: 000243838600014

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