We also used published gag and gp41 polymorphism data to highlight mutations displaying a high selection index, defined as changing from a conserved or common amino acid variant to an uncommon amino acid variant. We quantified nonsynonymous and synonymous mutations in both genes and identified sites exhibiting signal for directional or diversifying selection. To identify gag and gp41 mutations under selective PI pressure, we recently sequenced gag and/or gp41 in 61 individuals with virological failure on a PI or a control nonnucleoside RT inhibitor (NNRTI) containing regimen 15.

Indeed, 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 4вЂ“ 11 and several studies of pseudotyped viruses reported that genetic loci in matrix (MA) gag 12, 13 and in the gp41 cytoplasmic domain (CD) 14 can reduce PI susceptibility in the absence of PI-resistance protease mutations. HIV-1 protease mutations responsible for protease inhibitor (PI) resistance are now uncommon in patients with virological failure on an initial PI-containing regimen, particularly regimens including pharmacologically-boosted lopinavir, atazanavir, or darunavir 1вЂ“ 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. 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. In this study, we generated site-specific amino acid profiles using gag and gp41 published sequences from 5,338 and 4,242 ART-naГЇve 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. 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. One proposed explanation is that HIV-1 gag or gp41 cytoplasmic domain mutations might also reduce PI susceptibility. Most HIV-1-infected individuals with virological failure on a pharmacologically-boosted protease inhibitor (PI) regimen do not develop PI-resistance protease mutations.

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