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Role of APOBEC3G/F-mediated hypermutation in the control of human immunodeficiency virus type 1 in elite suppressors.

ABSTRACT: While many studies show that the APOBEC3 family of cytidine deaminases can inhibit human immunodeficiency virus type 1 (HIV-1) replication, the clinical significance of this host defense mechanism is unclear. Elite suppressors are HIV-1-infected individuals who maintain viral loads below 50 copies/ml without antiretroviral therapy. To determine the role of APOBEC3G/F proteins in the control of viremia in these patients, we used a novel assay to measure the frequency of hypermutated proviral genomes. In most elite suppressors, the frequency was not significantly different than that observed in patients on highly active antiretroviral therapy. Thus, enhanced APOBEC3 activity alone cannot explain the ability of elite suppressors to control viremia.

SUBMITTER: Gandhi SK

PROVIDER: S-EPMC2259015 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

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Role of APOBEC3G/F-mediated hypermutation in the control of human immunodeficiency virus type 1 in elite suppressors.

Gandhi Shiv K SK Siliciano Janet D JD Bailey Justin R JR Siliciano Robert F RF Blankson Joel N JN

Journal of virology 20071212 6

While many studies show that the APOBEC3 family of cytidine deaminases can inhibit human immunodeficiency virus type 1 (HIV-1) replication, the clinical significance of this host defense mechanism is unclear. Elite suppressors are HIV-1-infected individuals who maintain viral loads below 50 copies/ml without antiretroviral therapy. To determine the role of APOBEC3G/F proteins in the control of viremia in these patients, we used a novel assay to measure the frequency of hypermutated proviral geno ...[more]

PMID: 18077705

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Project description:A subset of HIV-1-infected patients known as elite controllers or suppressors (ES) control the virus naturally. We have previously demonstrated sequence discordance between proviral and plasma gag clones in ES, much of which can be attributed to selective pressure from the host (J. R. Bailey, T. M. Williams, R. F. Siliciano, and J. N. Blankson, J. Exp. Med. 203:1357-1369, 2006). However, it is not clear whether ongoing viral replication continues in ES once the control of viremia has been established or whether selective pressure impacts this evolution. The cytotoxic T-lymphocyte (CTL) response in ES often targets Gag and frequently is superior to that of HIV-1 progressors, partially due to the HLA class I alleles B*57/5801 and B*27, which are overrepresented in ES. We therefore examined longitudinal plasma and proviral gag sequences from HLA-B*57/5801 and -B*27 ES. Despite the highly conserved nature of gag, we observed clear evidence of evolution in the plasma virus, largely due to synonymous substitutions. In contrast, evolution was rare in proviral clones, suggesting that ongoing replication in ES does not permit the significant reseeding of the latent reservoir. Interestingly, there was little continual evolution in CTL epitopes, and we detected de novo CTL responses to autologous viral mutants. Thus, some ES control viremia despite ongoing replication and evolution.

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