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

Kavidha Reddy; Cheryl A. Winkler; Lise Werner; Koleka P. Mlisana; Salim Abdool Karim; Thumbi Ndung'u

Title:
APOBEC3G expression is dysregulated in primary HIV-1 infection and polymorphic variants influence CD4+ T-cell counts and plasma viral load
Author(s):
Reddy, Kavidha
Winkler, Cheryl A.
Werner, Lise
Mlisana, Koleka P.
Abdool Karim, Salim
Ndung'u, Thumbi
Date:
Type:
Articles
Department:
Epidemiology
Volume:
24
Permanent URL:
Book/Journal Title:
AIDS
Abstract:
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 APOBEC3G in HIV-negative and HIV-positive primary infection samples. APOBEC3G variants were identified by DNA re-sequencing and TaqMan genotyping. RESULTS: We found no correlation between APOBEC3G 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. APOBEC3G 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 APOBEC3G 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 APOBEC3G transcription is rapidly downregulated upon HIV-1 infection. During primary infection, APOBEC3G 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-1 pathogenesis, although the mechanism remains unclear and warrants further investigation.
Subject(s):
Virology
Epidemiology
Publisher DOI:
http://dx.doi.org/10.1097/QAD.0b013e3283353bba
Item views:
143
Metadata:
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