Polymorphisms of CUL5 are associated with CD4+ T cell loss in HIV-1 infected individuals.
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.
An
Ping
P
Laboratory of Genomic Diversity, SAIC-Frederick, Incorporated, National Cancer Institute, Frederick, Maryland, United States of America.
Duggal
Priya
P
Wang
Li Hua
LH
O'Brien
Stephen J
SJ
Donfield
Sharyne
S
Goedert
James J
JJ
Phair
John
J
Buchbinder
Susan
S
Kirk
Gregory D
GD
Winkler
Cheryl A
CA
D001741:Black or African American; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D015331:Cohort Studies; D044842:Cullin Proteins / Q000235:genetics*; D017931:DNA Primers; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008137:Longitudinal Studies; D008212:Lymphocyte Depletion; D005810:Multigene Family; D020641:Polymorphism, Single Nucleotide
C496871:CUL5 protein, human; D044842:Cullin Proteins; D017931:DNA Primers