Genetic determinants in HIV-1 Gag and Env V3 are related to viral response to combination antiretroviral therapy with a protease inhibitor

Abstract

Objective To identify novel viral determinants in HIV-1 protease, Gag, and envelope V3 that relate to outcomes to initial protease inhibitor-based antiretroviral therapy. Design A longitudinal cohort study of protease inhibitor-naive, HIV-infected individuals was designed to identify genetic variables in viral Gag and envelope sequences associated with response to antiretroviral therapy. Methods Genetic and statistical models, including amino acid profiles, phylogenetic analyses, receiver operating characteristic analyses, and covariation analyses, were used to evaluate viral sequences and clinical variables from individuals who developed immune reconstitution with or without suppression of viral replication. Results Pretherapy chemokine (C–X–C motif) receptor 4-using V3 regions had significant associations with viral failure (P = 0.04). Amino acid residues in protease covaried with Gag residues, particularly in p7NC, independent of cleavage sites. Pretherapy V3 charge combined with p6Pol and p2/p7NC cleavage site genotypes produced the best three-variable model to predict viral suppression in 88% of individuals. Combinations of baseline CD4 cell percentage with genetic determinants in Gag–protease predicted viral fitness in 100% of individuals who failed to suppress viral replication. Conclusion Baseline genetic determinants in Gag p6Pol and p2/p7NC, as well as envelope, provide novel combinations of biomarkers for predicting emergence of viral resistance to initial therapy regimens.

Microbial translocation induces persistent macrophage activation unrelated to HIV-1 levels or T-cell activation following therapy

“…The divergence in sCD27 levels in post-ART viral success versus viral failure subjects may be linked to qualitative differences in HIV-1 phenotype and co-receptor utilization. HIV-1 isolated from subjects who suppress viremia primarily use only CCR5 co-receptor for target cell entry, while HIV-1 from viral failure subjects use both CCR5 and CXCR4 co-receptors before and after ART[33]. Persistently elevated sCD27 demonstrates that replication of drug-resistant HIV-1 induces some component of lymphocyte activation in spite of improved CD4 T cells counts and normal immune function[24], indicating that systemic immune activation and its consequences are complex and multifactorial.…”

“…[23, 24, 33]. Briefly, all HIV-1-infected subjects were infected perinatally and viral and immune outcomes were known.…”

“…Prior to ART, HIV-1 infected subjects had plasma viral loads ranging from 2.9 to 6.1 log 10 HIV-1 RNA copies/ml (median = 4.6 log 10 ). By 24 weeks of ART, all subjects experienced increased CD4% either with viral suppression [<400 viral RNA copies/ml plasma] that was sustained for 96 weeks or viral rebound [>400 viral RNA copies/ml plasma] (24 week median = 3.9 log 10 copies/ml; 96 week median = 4.0 log 10 copies/ml)[23, 24, 33]. …”

High-resolution deep sequencing reveals biodiversity, population structure, and persistence of HIV-1 quasispecies within host ecosystems

“…Assessments of biodiversity from deep sequencing data provide unprecedented views of the richness of immune loci in primates, zebra fish, and humans [17,18,26] or the complexity of microbiomes independent of an ability to culture microorganisms [21,24,25,29]. Biodiversity defines complexity within populations that extend beyond evaluations of diversity based on pairwise genetic distance, the major approach for analysis of small data sets of HIV-1 sequences from infected individuals [30,31]. Biodiversity within HIV-1 populations might reflect host environments, infection by circulating recombinant forms of HIV-1 or co-infection by multiple subtypes, and provide unique and sensitive biomarkers for changes in viral populations.…”

A Cleavage Enzyme-Cytometric Bead Array Provides Biochemical Profiling of Resistance Mutations in HIV-1 Gag and Protease

“…These primary mutations are followed by compensatory mutations distal to the active site, which improves protease catalytic efficiency, k cat / K M (9, 10). In addition to PR mutations enhancing drug resistance, viruses obtained from HAART experienced individuals have mutations in gag at protease cleavage sites (CS) as well as in gag non-cleavage site (NCS) locations (11-13). Some of the gag cleavage site mutations improve the catalytic efficiency of both wild type protease and drug-resistant proteases (10, 14, 15).…”