APOBEC3G genetic variants and their influence on the progression to AIDS

Abstract

The cytosine deaminase APOBEC3G, in the absence of the human immunodeficiency virus type 1 (HIV-1) accessory gene HIV-1 viral infectivity factor (vif), inhibits viral replication by introducing G-->A hypermutation in the newly synthesized HIV-1 DNA negative strand. We tested the hypothesis that genetic variants of APOBEC3G may modify HIV-1 transmission and disease progression. Single nucleotide polymorphisms were identified in the promoter region (three), introns (two), and exons (two). Genotypes were determined for 3,073 study participants enrolled in six HIV-AIDS prospective cohorts. One codon-changing variant, H186R in exon 4, was polymorphic in African Americans (AA) (f = 37%) and rare in European Americans (f < 3%) or Europeans (f = 5%). For AA, the variant allele 186R was strongly associated with decline in CD4 T cells (CD4 slope on square root scale: -1.86, P = 0.009), The 186R allele was also associated with accelerated progression to AIDS-defining conditions in AA. The in vitro antiviral activity of the 186R enzyme was not inferior to that of the common H186 variant. These studies suggest that there may be a modifying role of variants of APOBEC3G on HIV-1 disease progression that warrants further investigation.

FIG. 1.

Gene map, LD, and haplotypes of APOBEC3G. (a) Exon distribution (not to scale) and genomic locations of the SNPs. Coding exons are marked by shaded blocks, and the 5′ and 3′ untranslated regions are marked by white blocks. The SNPs were numbered according to the first base of the translation start site for those located in the putative promoter region, of reference sequence AL022318 for intronic SNPs, and of the amino acid sequence (NP_068594). (b) The six most frequent haplotypes and their frequencies in AA, EA, and Chinese (CH). (c) Detailed LD parameter D′ for the six SNPs in AA (below the diagonal) and EA (above the diagonal); **, P < 0.001; ***, P < 0.0001.

FIG. 2.

Kaplan-Meier survival curves of HIV-1 progression to AIDS-1987 after seroconversion for the three genotypes of APOBEC3G-H186R in AA. RH and Wald P values are from an adjusted Cox model analysis, and log rank P value is for the Kaplan-Meier statistic.

FIG. 3.

Antiviral activity of APOBEC3G 186H and 186R variants. (A) 293T cells were transfected with R9 HIV-1 or with the Vif-defective R9Δvif proviral clone in the presence of empty vector, wt hAPOBEC3G (H186R), or 186R APOBEC3G-expressing vector. Supernatant was filtered, and viral titer was scored by infecting HeLa-CD4-LacZ reporter cells not expressing APOBEC3G. Virion infectivity is normalized for particle amount, as measured by RT activity assay. (B) In a second experiment, 293T cells were transfected with R9Δvif in the presence of four different doses of either an empty vector, wt hAPOBEC3G, or 186R APOBEC3G-expressing vector. The four ratios of APOBEC3G to R9Δvif are 0.5 (dark grey), 1 (light grey), 2 (white), and 3 (stippled). Analyses were done in duplicate, with bars representing the standard deviations.