Marine Perrier1, Louise Castain2, Leslie Regad3, Eve Todesco2, Roland Landman4, Benoit Visseaux1, Yazdan Yazdanpanah4, Christophe Rodriguez5, Véronique Joly4, Vincent Calvez2, Anne-Geneviève Marcelin2, Diane Descamps1, Charlotte Charpentier1. 1. IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, AP-HP, Laboratoire de Virologie, Hôpital Bichat, AP-HP, Paris, France. 2. Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), AP-HP, Hôpital Pitié-Salpêtrière, Laboratoire de Virologie, F-75013 Paris, France. 3. Sorbonne Paris Cité, Université Paris-Diderot, CNRS, INSERM, Biologie Fonctionnelle et Adaptative UMR 8251, Computational Modeling of Protein Ligand Interactions U1133, Paris, France. 4. IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, AP-HP, Service de Maladies Infectieuses et Tropicales, Hôpital Bichat, AP-HP, Paris, France. 5. INSERM U955 Eq18, CNR hépatites virales B, C et delta, Laboratoire de Virologie, Hôpital Henri Mondor, AP-HP, Paris, France.
Abstract
OBJECTIVES: 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. PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
OBJECTIVES: 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. PATIENTS AND METHODS: One hundred and fifty-four HIV-infected ART-naivepatients 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. RESULTS: 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). CONCLUSIONS: 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.
Authors: Beauty E Omoruyi; David I Ighodaro; Anthony J Afolayan; Graeme Bradley Journal: Evid Based Complement Alternat Med Date: 2020-06-07 Impact factor: 2.629
Authors: Oscar Blanch-Lombarte; José R Santos; Ruth Peña; Esther Jiménez-Moyano; Bonaventura Clotet; Roger Paredes; Julia G Prado Journal: J Antimicrob Chemother Date: 2020-09-01 Impact factor: 5.790
Authors: Yuta Hikichi; Rachel Van Duyne; Phuong Pham; Jennifer L Groebner; Ann Wiegand; John W Mellors; Mary F Kearney; Eric O Freed Journal: mBio Date: 2021-01-12 Impact factor: 7.867