A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy
Roger Paredes, Maria Carmen Puertas, Wendy Bannister, Mónica Kisic, Alessandro Cozzi-Lepri, Christian Pou, Rocío Bellido, Gilberto Betancor, Johannes Bogner, Panagiotis Gargalianos, Dénes Bánhegyi, Bonaventura Clotet, Jens Lundgren, Luis Menéndez-Arias, Javier Martinez-Picado, EuroSIDA Study Group, M Losso, C Elias, N Vetter, R Zangerle, I Karpov, A Vassilenko, V M Mitsura, O Suetnov, N Clumeck, S De Wit, B Poll, R Colebunders, L Vandekerckhove, V Hadziosmanovic, K Kostov, J Begovac, L Machala, H Rozsypal, D Sedlacek, J Nielsen, G Kronborg, T Benfield, M Larsen, J Gerstoft, T Katzenstein, A-B E Hansen, P Skinhøj, C Pedersen, L Oestergaard, K Zilmer, M Ristola, C Katlama, J-P Viard, P-M Girard, J M Livrozet, P Vanhems, C Pradier, F Dabis, D Neau, J Rockstroh, R Schmidt, J van Lunzen, O Degen, H J Stellbrink, S Staszewski, G Fätkenheuer, J Kosmidis, P Gargalianos, G Xylomenos, J Perdios, G Panos, A Filandras, E Karabatsaki, H Sambatakou, D Banhegyi, F Mulcahy, I Yust, D Turner, M Burke, S Pollack, G Hassoun, S Maayan, S Vella, R Esposito, I Mazeu, C Mussini, C Arici, R Pristera, F Mazzotta, A Gabbuti, V Vullo, M Lichtner, A Chirianni, E Montesarchio, M Gargiulo, G Antonucci, F Iacomi, P Narciso, C Vlassi, M Zaccarelli, A Lazzarin, R Finazzi, M Galli, A Ridolfo, A d'Arminio, B Rozentale, P Aldins, S Chaplinskas, R Hemmer, T Staub, P Reiss, V Ormaasen, A Maeland, J Brunn, B Knysz, J Gasiorowski, A Horban, E Bakowska, D Prokopowicz, R Flisiak, A Boron-Kaczmarska, M Pynka, M Beniowski, E Mularska, H Trocha, E Jablonowska, E Malolepsza, K Wojcik, F Antunes, E Valadas, K Mansinho, F Maltez, D Duiculescu, A Rakhmanova, E Vinogradova, S Buzunova, D Jevtovic, M Mokrás, D Staneková, J Tomazic, J González-Lahoz, V Soriano, L Martin-Carbonero, P Labarga, S Moreno, B Clotet, A Jou, R Paredes, C Tural, J Puig, I Bravo, J M Gatell, J M Miró, P Domingo, M Gutierrez, G Mateo, M A Sambeat, A Karlsson, P O Persson, B Ledergerber, R Weber, P Francioli, M Cavassini, B Hirschel, E Boffi, H Furrer, M Battegay, L Elzi, E Kravchenko, N Chentsova, G Kutsyna, S Servitskiy, M Krasnov, S Barton, A M Johnson, D Mercey, A Phillips, M A Johnson, M Murphy, J Weber, G Scullard, M Fisher, C Leen, J Gatell, B Gazzard, A Horban, B Ledergerber, M Losso, J Lundgren, A d'Arminio Monforte, C Pedersen, A Phillips, A Rakhmanova, P Reiss, M Ristola, J Rockstroh, S De Wit, J Lundgren, O Kirk, A Mocroft, A Cozzi-Lepri, D Grint, M Ellefson, D Podlekareva, J Kjaer, L Peters, J Reekie, J Kowalska, J Tverland, A H Fischer, J Nielsen, Roger Paredes, Maria Carmen Puertas, Wendy Bannister, Mónica Kisic, Alessandro Cozzi-Lepri, Christian Pou, Rocío Bellido, Gilberto Betancor, Johannes Bogner, Panagiotis Gargalianos, Dénes Bánhegyi, Bonaventura Clotet, Jens Lundgren, Luis Menéndez-Arias, Javier Martinez-Picado, EuroSIDA Study Group, M Losso, C Elias, N Vetter, R Zangerle, I Karpov, A Vassilenko, V M Mitsura, O Suetnov, N Clumeck, S De Wit, B Poll, R Colebunders, L Vandekerckhove, V Hadziosmanovic, K Kostov, J Begovac, L Machala, H Rozsypal, D Sedlacek, J Nielsen, G Kronborg, T Benfield, M Larsen, J Gerstoft, T Katzenstein, A-B E Hansen, P Skinhøj, C Pedersen, L Oestergaard, K Zilmer, M Ristola, C Katlama, J-P Viard, P-M Girard, J M Livrozet, P Vanhems, C Pradier, F Dabis, D Neau, J Rockstroh, R Schmidt, J van Lunzen, O Degen, H J Stellbrink, S Staszewski, G Fätkenheuer, J Kosmidis, P Gargalianos, G Xylomenos, J Perdios, G Panos, A Filandras, E Karabatsaki, H Sambatakou, D Banhegyi, F Mulcahy, I Yust, D Turner, M Burke, S Pollack, G Hassoun, S Maayan, S Vella, R Esposito, I Mazeu, C Mussini, C Arici, R Pristera, F Mazzotta, A Gabbuti, V Vullo, M Lichtner, A Chirianni, E Montesarchio, M Gargiulo, G Antonucci, F Iacomi, P Narciso, C Vlassi, M Zaccarelli, A Lazzarin, R Finazzi, M Galli, A Ridolfo, A d'Arminio, B Rozentale, P Aldins, S Chaplinskas, R Hemmer, T Staub, P Reiss, V Ormaasen, A Maeland, J Brunn, B Knysz, J Gasiorowski, A Horban, E Bakowska, D Prokopowicz, R Flisiak, A Boron-Kaczmarska, M Pynka, M Beniowski, E Mularska, H Trocha, E Jablonowska, E Malolepsza, K Wojcik, F Antunes, E Valadas, K Mansinho, F Maltez, D Duiculescu, A Rakhmanova, E Vinogradova, S Buzunova, D Jevtovic, M Mokrás, D Staneková, J Tomazic, J González-Lahoz, V Soriano, L Martin-Carbonero, P Labarga, S Moreno, B Clotet, A Jou, R Paredes, C Tural, J Puig, I Bravo, J M Gatell, J M Miró, P Domingo, M Gutierrez, G Mateo, M A Sambeat, A Karlsson, P O Persson, B Ledergerber, R Weber, P Francioli, M Cavassini, B Hirschel, E Boffi, H Furrer, M Battegay, L Elzi, E Kravchenko, N Chentsova, G Kutsyna, S Servitskiy, M Krasnov, S Barton, A M Johnson, D Mercey, A Phillips, M A Johnson, M Murphy, J Weber, G Scullard, M Fisher, C Leen, J Gatell, B Gazzard, A Horban, B Ledergerber, M Losso, J Lundgren, A d'Arminio Monforte, C Pedersen, A Phillips, A Rakhmanova, P Reiss, M Ristola, J Rockstroh, S De Wit, J Lundgren, O Kirk, A Mocroft, A Cozzi-Lepri, D Grint, M Ellefson, D Podlekareva, J Kjaer, L Peters, J Reekie, J Kowalska, J Tverland, A H Fischer, J Nielsen
Abstract
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 = .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.
Source: PubMed