Human Immunodeficiency Virus (HIV) Type 1 Proviral Hypermutation Correlates with CD4 Count in HIV-Infected Women from Kenya

Abstract

APOBEC3G is an important innate immune molecule that causes human immunodeficiency virus type 1 (HIV-1) hypermutation, which can result in detrimental viral genome mutations. The Vif protein of wild-type HIV-1 counteracts APOBEC3G activity by targeting it for degradation and inhibiting its incorporation into viral particles. Additional APOBEC cytidine deaminases have been identified, such as APOBEC3F, which has a similar mode of action but different sequence specificity. A relationship between APOBEC3F/G and HIV disease progression has been proposed. During HIV-1 sequence analysis of the vpu/env region of 240 HIVinfected subjects from Nairobi, Kenya, 13 drastically hypermutated proviral sequences were identified. Sequences derived from plasma virus, however, lacked hypermutation, as did proviral vif. When correlates of disease progression were examined, subjects with hypermutated provirus were found to have significantly higher CD4 counts than the other subjects. Furthermore, hypermutation as estimated by elevated adenine content positively correlated with CD4 count for all 240 study subjects. The sequence context of the observed hypermutation was statistically associated with APOBEC3F/G activity. In contrast to previous studies, this study demonstrates that higher CD4 counts correlate with increased hypermutation in the absence of obvious mutations in the APOBEC inhibiting Vif protein. This strongly suggests that host factors, such as APOBEC3F/G, are playing a protective role in these patients, modulating viral hypermutation and host disease progression. These findings support the potential of targeting APOBEC3F/G for therapeutic purposes.

Human immunodeficiency virus type 1 long-term non-progressors: the viral, genetic and immunological basis for disease non-progression

“…APOBEC3G-induced hypermutations in vpu/env proviral DNA have been correlated with higher CD4 + Tcell counts (P50.042) in a large cohort of HIV-infected Kenyan women (n5208) (Land et al, 2008). Other APOBEC3G polymorphisms are associated with increased rates of disease progression, as demonstrated by An et al (2004) in their study of 3073 HIV-1-infected subjects from six HIV-AIDS prospective cohorts.…”

APOBEC proteins and intrinsic resistance to HIV-1 infection

“…A third possibility is genetic variation among individuals, and polymorphisms in A3G or cullin5 have been correlated with differences in the rates of disease progression . Finally, though not addressing cause versus effect, increased CD4 T-cell counts and decreased virus loads have each been correlated with the burden of hypermutated (inactivated) HIV-1 sequences (Pace et al 2006;Land et al 2008). It is worth noting, however, that not only does a good deal of controversy remain concerning the conclusions of some of these studies (Do et al 2005;Gandhi et al 2008) but also unambiguously establishing causality for these in vivo phenotypes can be expected to be challenging.…”

“…The consensus dinucleotide target for deamination is also different with 5 0 -TC (substrate cytidine underlined) serving as the preferred site for A3F (Bishop et al 2004a;Liddament et al 2004;Wiegand et al 2004), rather than the 5 0 -CC defined for A3G ( §5). Numerous analyses of HIV-1 sequences recovered from HIV-1 infected persons reveal the frequent presence of G-to-A hypermutated viral DNA ( Fitzgibbon et al 1993;Vartanian et al 1994;Janini et al 2001;Kieffer et al 2005;Pace et al 2006;Kijak et al 2008;Land et al 2008). Further inspection of the local sequence context of such mutations reveals 5 0 -GG (plus sense sequence) as the predominant target and 5 0 -GA as the second most likely substrate.…”

APOBEC3F Determinants of HIV-1 Vif Sensitivity

“…APOBEC3 proteins deaminate DNA cytosines to uracils, which during synthesis of the cDNA strand, provides a template for adenines, resulting in the characteristic Gto-A hypermutation observed in HIV-1 proviral sequences (3)(4)(5). These mutations can be detrimental to the virus (6,7).…”