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A376s in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy

par Paredes, Roger;Puertas, Maria Carmen;Bannister, Wendy;Kisic, Mónica;Cozzi-Lepri, Alessandro;Pou, Christian;Bellido, Rocío;Betancor, Gilberto;Bogner, Johannes;Gargalianos, Panagiotis;Bánhegyi, Dénes;Clotet, Bonaventura;Lundgren, Jens D;Menéndez-Arias, Luis;Martinez-Picado, Javier;Losso, Marcello;Elias, Christopher;Vetter, Norbert;Zangerle, Robert;Karpov, Igor;Vassilenko, A.;Mitsura, Victor;Suetnov, Oleg;Clumeck, Nathan ;De Wit, Stéphane ;Poll, Bénédicte;Colebunders, Robert Leon;Vandekerckhove, Linos;Hadziosmanovic, Vesna;Kostov, Kostadin;Begovac, Josip;Machala, Ladislav;Rozsypal, Hanuš;Sedlacek, Dalibor;Nielsen, Jens Ole;Kronborg, Gitte;Benfield, Thomas;Larsen, Mette Vang
Référence The Journal of infectious diseases, 204, 5, page (741-752)
Publication Publié, 2011-09

Article révisé par les pairs

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Résumé :

Background. The clinical relevance of mutations in the connection subdomain and the ribonuclease (RNase) H domain of HIV-1 reverse transcriptase (RT) is uncertain. Methods. The risk of virological failure to nonnucleoside RT inhibitor (NNRTI)-based antiretroviral therapy (ART) was evaluated in NNRTI-naive patients who started NNRTIs in the EuroSIDA study after July 1997 according to preexisting substitutions in the connection subdomain and the RNase H domain of HIV-1 RT. An observed association between A376S and virological failure was further investigated by testing in vitro NNRTI susceptibility of single site-directed mutants and patient-derived recombinant viruses. Enzymatic assays also determined the effects of A376S on nevirapine and template-primer binding to HIV-1 RT. Results. Virological failure occurred in 142 of 287 (49%) individuals: 77 receiving nevirapine (67%) and 65 receiving efavirenz (38%) (P < .001). Preexisting A376S was associated with an increased risk of virological failure to nevirapine (relative hazard [RH] = 10.4; 95% confidence interval [CI], 2.0-54.7), but it did not affect efavirenz outcome the same way (RH = 0.5; 95% CI, 0.1-2.2) (P value for interaction 5 .013). A376S conferred selective low-level nevirapine resistance in vitro, and led to greater affinity for double-stranded DNA. Conclusions. The A376S substitution in the connection subdomain of HIV-1 RT causes selective nevirapine resistance and confers an increased risk of virological failure to nevirapine-based ART. © The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.