Abstract
Several groups have proposed that genotypic determinants in gag and the gp41 cytoplasmic domain (gp41-CD) reduce protease inhibitor (PI) susceptibility without PI-resistance mutations in protease. However, no gag and gp41-CD mutations definitively responsible for reduced PI susceptibility have been identified in individuals with virological failure (VF) while receiving a boosted PI (PI/r)-containing regimen. To identify gag and gp41 mutations under selective PI pressure, we sequenced gag and/or gp41 in 61 individuals with VF on a PI/r (n = 40) or NNRTI (n = 20) containing regimen. We quantified nonsynonymous and synonymous changes in both genes and identified sites exhibiting signal for directional or diversifying selection. We also used published gag and gp41 polymorphism data to highlight mutations displaying a high selection index, defined as changing from a conserved to an uncommon amino acid. Many amino acid mutations developed in gag and in gp41-CD in both the PI- and NNRTI-treated groups. However, in neither gene, were there discernable differences between the two groups in overall numbers of mutations, mutations displaying evidence of diversifying or directional selection, or mutations with a high selection index. If gag and/or gp41 encode PI-resistance mutations, they may not be confined to consistent mutations at a few sites.
Highlights
HIV-1 can develop resistance to protease inhibitors (PIs) as a result of protease mutations that reduce PI binding affinity or compensate for the reduced fitness associated with PI binding site mutations[1]
To identify mutations that may have resulted from cytotoxic T lymphocyte (CTL) selective pressure, we looked up each mutation in the LANL Immunology HIV Database CTL/CD8+ Epitope Summary file[19]
No gag changes have been consistently observed in individuals with virological failure (VF) while receiving a PI-containing regimen[40], and there have been no studies of gp41-CD sequences in viruses from patients before and after receiving a PI-containing regimen
Summary
HIV-1 can develop resistance to protease inhibitors (PIs) as a result of protease mutations that reduce PI binding affinity or compensate for the reduced fitness associated with PI binding site mutations[1]. The first explanation is that PI-resistance mutations in protease develop only in viruses exposed to a narrow window of suboptimal drug concentrations that both exert selective pressure on the virus and allow virus replication[6]. This explanation is supported by the observations that patients receiving PI-containing regimens are at reduced risk of developing NRTI-resistance mutations[7, 8], and that most patients with VF on an initial PI-containing regimen but without PI-resistance protease mutations achieve virological re-suppression with improved adherence alone[9,10,11]. We sequenced paired viruses from a control group of individuals that received a non-nucleoside RT inhibitor (NNRTI)-containing regimen as first-line therapy and experienced VF
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