Abstract

Most HIV-1-infected individuals with virological failure on a pharmacologically-boosted protease inhibitor (PI) regimen do not develop PI-resistance protease mutations. One proposed explanation is that HIV-1 gag or gp41 cytoplasmic domain mutations might also reduce PI susceptibility. In a recent study of paired gag and gp41 sequences from individuals with virological failure on a PI regimen, we did not identify PI-selected mutations and concluded that if such mutations existed, larger numbers of paired sequences from multiple studies would be needed for their identification. In this study, we generated site-specific amino acid profiles using gag and gp41 published sequences from 5,338 and 4,242 ART-naïve individuals, respectively, to assist researchers identify unusual mutations arising during therapy and to provide scripts for performing established and novel maximal likelihood estimates of dN/dS substitution rates in paired sequences. The pipelines used to generate the curated sequences, amino acid profiles, and dN/dS analyses will facilitate the application of consistent methods to paired gag and gp41 sequence datasets and expedite the identification of potential sites under PI-selection pressure.

Highlights

  • HIV-1 protease mutations responsible for protease inhibitor (PI) resistance are uncommon in patients with virological failure on an initial PI-containing regimen, regimens including pharmacologically-boosted lopinavir, atazanavir, or darunavir[1,2,3] One explanation for the infrequent occurrence of PI-resistance mutations in protease is that mutations outside of protease might reduce PI susceptibility even in the absence of primary PI resistance protease mutations

  • Many studies have reported that gag cleavage and non-cleavage site mutations may compensate for the reduced fitness associated with primary PI-resistance protease mutations[4,5,6,7,8,9,10,11] and several studies of pseudotyped viruses reported that genetic loci in matrix (MA) gag[12,13] and in the gp[41] cytoplasmic domain (CD)[14] can reduce PI susceptibility in the absence of PI-resistance protease mutations

  • The sequences described in our previous manuscript were obtained from HIV-1-infected individuals in Northern California who had genotypic resistance tests performed between April 2001 and June 2013 and from participants in the ACTG A5202 clinical trial[3,15]

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Summary

Background & Summary

HIV-1 protease mutations responsible for protease inhibitor (PI) resistance are uncommon in patients with virological failure on an initial PI-containing regimen, regimens including pharmacologically-boosted lopinavir, atazanavir, or darunavir[1,2,3] One explanation for the infrequent occurrence of PI-resistance mutations in protease is that mutations outside of protease might reduce PI susceptibility even in the absence of primary PI resistance protease mutations. In neither gene, were there discernible 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 Based on this previous study, we concluded that if gag and/or gp[41] encoded PI-resistance mutations, they might not be confined to repeated mutations at a few sites, and that multiple studies with large numbers of paired sequences from individuals with virological failure on a PI-containing regimen would need to be pooled to identify such mutations. The selection index analyses, in particular, require additional exposition because they used data derived from the curation and annotation of gag and gp[41] sequences from more than 500 GenBank submission sets and/or peer-reviewed publications to determine the polymorphism rates at each gag and gp[41] position The annotation of these references according to the treatment status of the individuals in the references is included as part of this manuscript’s Data Citation. The HyPhy scripts described in this manuscript make it possible to exactly replicate each of the maximum likelihood estimates of the ratio of nonsynonymous and synonymous substitution rates presented in our original manuscript

Methods
E NWGM RGG IAASAQRP GQ I E R DM PTSAAR
Findings
H S CV L TV ALQT
Full Text
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