HIV-1 protease, Gag and gp41 baseline substitutions associated with virological response to a PI-based regimen

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.

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.

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).

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.