Biology Faculty Articles
Document Type
Article
Publication Date
1-2007
Publication Title
PLoS ONE
ISSN
1932-6203
Volume
3
Issue/No.
1 e19
First Page
123
Last Page
132
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.
Additional Comments
National Cancer Institute contract #: N01-CO-12400; National Institute on Drug Abuse grant #: DA-04334
NSUWorks Citation
An, Ping; Priya Duggal; Li Hua Wang; Stephen J. O'Brien; Sharyne Donfield; James J. Goedert; John Phair; Susan Buchbinder; Gregory D. Kirk; and Cheryl Winkler. 2007. "Polymorphisms of CUL5 are Associated with CD4+ T Cell Loss in HIV-1 Infected Individuals." PLoS ONE 3, (1 e19): 123-132. https://nsuworks.nova.edu/cnso_bio_facarticles/781
ORCID ID
0000-0001-7353-8301
ResearcherID
N-1726-2015
Included in
Genetics and Genomics Commons, Immunology and Infectious Disease Commons, Medicine and Health Sciences Commons
Comments
©2007 An et al. This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.