HIV-1 Gag mutations alone are sufficient to reduce darunavir susceptibility during virological failure to boosted PI therapy
Blanch-Lombarte, Oscar (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Santos, José Ramón (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Peña, Ruth (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Jiménez Moyano, Esther (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Clotet Sala, Bonaventura (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Paredes, Roger (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Prado, Julia G. (Institut Germans Trias i Pujol)
Universitat Autònoma de Barcelona

Date:	2020
Abstract:	Virological failure (VF) to boosted PIs with a high genetic barrier is not usually linked to the development of resistance-associated mutations in the protease gene. From a cohort of 520 HIV-infected subjects treated with lopinavir/ritonavir or darunavir/ritonavir monotherapy, we retrospectively identified nine patients with VF. We sequenced the HIV-1 Gag-protease region and generated clonal virus from plasma samples. We characterized phenotypically clonal variants in terms of replicative capacity and susceptibility to PIs. Also, we used VESPA to identify signature mutations and 3D molecular modelling information to detect conformational changes in the Gag region. All subjects analysed harboured Gag-associated polymorphisms in the absence of resistance mutations in the protease gene. Most Gag changes occurred outside Gag cleavage sites. VESPA analyses identified K95R and R286K (P < 0. 01) as signature mutations in Gag present at VF. In one out of four patients with clonal analysis available, we identified clonal variants with high replicative capacity and 8- to 13-fold reduction in darunavir susceptibility. These clonal variants harboured K95R, R286K and additional mutations in Gag. Low susceptibility to darunavir was dependent on the Gag sequence context. All other clonal variants analysed preserved drug susceptibility and virus replicative capacity. Gag mutations may reduce darunavir susceptibility in the absence of protease mutations while preserving viral fitness. This effect is Gag-sequence context dependent and may occur during boosted PI failure.
Grants:	Instituto de Salud Carlos III CPII15-00014 Agència de Gestió d'Ajuts Universitaris i de Recerca 2018-FI-B-00582 Instituto de Salud Carlos III RD16-0025-0041
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Antiretroviral Therapy ; Darunavir ; HIV-1 ; HIV Infections ; Humans ; Viral Load
Published in:	Journal of antimicrobial chemotherapy, Vol. 75 (june 2020) , p. 2535-2546, ISSN 1460-2091

DOI: 10.1093/jac/dkaa228
PMID: 32556165

12 p, 653.9 KB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Articles > Research articles
Articles > Published articles