APOBEC3G expression is dysregulated in primary HIV-1 infection and polymorphic variants influence CD4+ T-cell counts and plasma viral load

Objectives: In the absence of HIV-1 virion infectivity factor (Vif), cellular cytosine deaminases such as apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G) inhibit the virus by inducing hypermutations on viral DNA, among other mechanisms of action. We investigated the association of APOBEC3G mRNA levels and genetic variants on HIV-1 susceptibility, and early disease pathogenesis using viral load and CD4(+) T-cell counts as outcomes. Methods: Study participants were 250 South African women at high risk for HIV-1 subtype C infection. We used real-time PCR to measure the expression of APOBEC3C in HIV-negative and HIV-positive primary infection samples. APOBEC3C variants were identified by DNA re-sequencing and TaqMan genotyping. Results: We found no correlation between APOBEC3C expression levels and plasma viral loads (r=0.053, P=0.596) or CD4(+) T-cell counts (r=0.030, P=0.762) in 32 seroconverters. APOBEC3C expression levels were higher in HIV-negative individuals as compared with HIV-positive individuals (P<0.0001), including matched pre and postinfection samples from the same individuals (n=13, P<0.0001). Twenty-four single nucleotide polymorphisms, including eight novel, were identified within APOBEC3C by re-sequencing and genotyping. The H186R mutation, a codon-changing variant in exon 4, and a 3' extragenic Mutation (rs35228531) were associated with high viral loads (P=0.0097 and P < 0.0001) and decreased CD4(+) T-cell levels (P=0.0081 and P < 0.0001), respectively. Conclusion: These data suggest that APOBEC3C transcription is rapidly downregulated upon HIV-1 infection. During primary infection, APOBEC3C expression levels in peripheral blood mononuclear cells do not correlate with viral loads or CD4(+) T-cell counts. Genetic variation of APOBEC3G may significantly affect early HIV-11 pathogenesis, although the mechanism remains unclear and warrants further investigation. (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

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