Polymorphisms of CUL5 Are Associated with CD4+ T Cell Loss in HIV-1 Infected Individuals

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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. Human apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 G (Apobec3G) is an innate antiviral protein that inhibits HIV type 1 (HIV-1) replication by causing deleterious mutations in the HIV-1 genome. Unfortunately, HIV-1 has a strategy to defeat the antiviral activity of Apobec3G. The HIV-1 viral infectivity factor (Vif) binds to Apobec3G leading to the degradation of Apobec3G through a complex containing Cullin 5 and the proteins Elongin B and Elongin C. Since Cullin 5 directly interacts with Vif and is critical to the Apobec3G degradation pathway, the authors asked if genetic variation of CUL5 could tip the balance between HIV-1 and Apobec3G and modify the course of HIV-1 infection. They showed that genetic variation in the CUL5 gene encoding Cullin 5 affected the rate of CD4+ T cell loss in patients infected with HIV-1. CUL5 haplotypes formed two clusters of evolutionarily related haplotypes with opposing effects—cluster I delayed and the cluster II accelerated CD4+ T cell loss. The effect was mainly attributable to a single haplotype or its tagging-SNP, which demonstrated differential binding of transcription factors. This finding highlights the epidemiologic importance of the HIV-1 and Cullin 5 interaction and suggests that the factors in the HIV-1 Vif-Apobec3G degradation pathway may be targets for antiviral drugs.