Gag Mutations Can Impact Virological Response to Dual-Boosted Protease Inhibitor Combinations in Antiretroviral-Naïve HIV-Infected Patients

Abstract

ANRS 127 was a randomized pilot trial involving naïve patients receiving two dual-boosted protease inhibitor (PI) combinations. Virological response, defined as a plasma HIV RNA level of <50 copies/ml at week 16, occurred in only 41% patients. Low baseline plasma HIV RNA level was the only significant predictor of virological response. The purpose of this study was to investigate the impact on virological response of pretherapy mutations in cleavage sites of gag, gag-pol, and the gag-pol frameshift region. The whole gag gene and protease-coding region were amplified and sequenced at baseline and at week 16 for 48 patients still on the allocated regimen at week 16. No major PI resistance-associated mutations were detected either at baseline or in the 26 patients who did not achieve virological response at week 16. Baseline cleavage site substitutions in the product of the gag open reading frame at positions 128 (p17/p24) (P ‫؍‬ 0.04) and 449 (p1/p6 gag ) (P ‫؍‬ 0.01) were significantly more frequent in those patients not achieving virological response. Conversely, baseline cleavage site mutation at position 437 (TFP/p6 pol ) was associated with virological response (P ‫؍‬ 0.04). In multivariate analysis adjusted for baseline viral load, these 3 substitutions remained independently associated with virological response. We demonstrated here, in vivo, an impact of baseline polymorphic gag mutations on virological response in naïve patients receiving a combination of two protease inhibitors. However, it was not possible to link the substitutions selected under PI selective pressure with virological failure.

Mutations in Multiple Domains of Gag Drive the Emergence of In Vitro Resistance to the Phosphonate-Containing HIV-1 Protease Inhibitor GS-8374

“…This observation was supported by a subsequent study demonstrating that mutations at positions 431 and 437 are commonly found in highly PI-experienced patients and can contribute directly to PI resistance (26). On the other hand, Larrouy et al detected TFP-p6* mutations D437N and/or L441P in a large group of PI-naive patients (37). Notably, the baseline prevalences of either Asp or Gln at codon 437 and of either Leu or Pro at codon 441 were relatively equal, indicating a possible polymorphism associated with these sites.…”

“…This is different from most of the previous studies reporting Gag-associated resistance changes, where alterations contributing significantly to PI resistance were mostly traced to the C terminus of the polyprotein and mapped to the vicinity of Gag cleavage sites (26,37). In contrast, mutations in MA and CA selected under GS-8374 drug pressure were mostly distant from the Gag cleavage sites.…”

Three Residues in HIV-1 Matrix Contribute to Protease Inhibitor Susceptibility and Replication Capacity

“…In this study, by 16 weeks of treatment, 26 patients did not have viral load below 50 copies per ml and were therefore defined as failing therapy. Nucleotide sequence analysis of the HIV protease from these patients did not reveal any known PI resistance mutations, suggesting that determinants of PI therapy failure can lie outside of the protease gene (17). Another clinical trial of PI monotherapy (MONARK) also suggests that determinants of PI therapy failure are not fully understood, since of 33 patients failing PI monotherapy, only 5 had known major PI resistance mutations.…”

HIV Protease Inhibitor Resistance

“…Several studies evaluated the natural variation within Gag and its cleavage sites (Kolli et al 2009;Côté et al 2001;de Oliveira et al 2003;Verheyen et al 2009Verheyen et al , 2010Larrouy et al 2010;Bally et al 2000;Lambert-Niclot et al 2012) and suggest that the variation in HIV-1 non-B subtypes is greater than in subtype B (de Oliveira et al 2003;Verheyen et al 2009;Larrouy et al 2011a). The level of conservation differs dramatically between the different CS as within CS (Fig.…”