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- Title
HIV-1 protease, Gag and gp41 baseline substitutions associated with virological response to a PI-based regimen.
- Authors
Perrier, Marine; Castain, Louise; Regad, Leslie; Todesco, Eve; Landman, Roland; Visseaux, Benoit; Yazdanpanah, Yazdan; Rodriguez, Christophe; Joly, Véronique; Calvez, Vincent; Marcelin, Anne-Geneviève; Descamps, Diane; Charpentier, Charlotte
- Abstract
<bold>Objectives: </bold>To assess, at ART initiation, the impact of baseline substitutions in protease, Gag and gp41 regions on the virological response to a first-line PI-based regimen.<bold>Patients and Methods: </bold>One hundred and fifty-four HIV-infected ART-naive patients initiating a PI-based regimen including darunavir (n = 129) or atazanavir (n = 25) were assessed, including 36 experiencing virological failure (VF). Whole pol, gag and gp41 genes were sequenced at ART baseline by ultra-deep sequencing (UDS) using Illumina® technology. Supervised data-mining analyses were performed to identify mutations associated with virological response. Structural analyses were performed to assess the impact of mutations on protease conformation.<bold>Results: </bold>UDS was successful in 127, 138 and 134 samples for protease, Gag and gp41, respectively (31% subtype B and 38% CRF02_AG). Overall, T4A and S37T mutations in protease were identified as being associated with VF (P = 0.02 and P = 0.005, respectively). Among CRF02_AG sequences, I72M and E21D mutations were associated with VF (P = 0.03 for both). They all induced some conformational changes of some protease side-chain residues located near mutated residues. In Gag, mutations associated with VF were G62D, N315H and Y441S (P = 0.005, P = 0.007 and P = 0.0003, respectively). All were localized outside Gag cleavage sites (G62D, matrix; N315H, capsid; and Y441S, p1). In gp41, the I270T mutation, localized in the cytoplasmic tail, was associated with VF (P = 0.003), and the I4L mutation, in the fusion peptide, was associated with virological success (P = 0.004).<bold>Conclusions: </bold>In this study, new baseline substitutions in Gag, protease and g41, potentially impacting PI-based regimen outcome, were evidenced. Phenotypic analyses are required to confirm their role in the PI-resistance mechanism.
- Subjects
PROTEOLYTIC enzymes; VIROLOGY; ENDOPEPTIDASES; GENETIC mutation; PHENOTYPES
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2019, Vol 74, Issue 6, p1679
- ISSN
0305-7453
- Publication type
journal article
- DOI
10.1093/jac/dkz043