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

Paredes, R.; Puertas, M.C.; Bannister, W.; Kisic, M.; Cozzi-Lepri, A.; Pou, C.; Bellido, R.; Betancor, G.; Bogner, J.; Gargalianos, P.; Banhegyi, D.; Clotet, B.; Lundgren, J.; Menendez-Arias, L.; Martinez-Picado, J.; Losso, M.; Elias, C.; Vetter, N.; Zangerle, R.; Karpov, I.; Vassilenko, A.; Mitsura, V.M.; Suetnov, O.; Clumeck, N.; De Wit, S.; Poll, B.; Colebunders, R.; Vandekerckhove, L.; Hadziosmanovic, V.; Kostov, K.; Begovac, J.; Machala, L.; Rozsypal, H.; Sedlacek, D.; Nielsen, J.; Kronborg, G.; Benfield, T.; Larsen, M.; Gerstoft, J.; Katzenstein, T.; Hansen, A.-.E.; Skinhoj, P.; Pedersen, C.; Oestergaard, L.; Zilmer, K.; Smidt, J.; Ristola, M.; Katlama, C.; Viard, J.-.; Girard, P.-.; Livrozet, J.M.; Vanhems, P.; Pradier, C.; Dabis, F.; Neau, D.; Rockstroh, J.; Schmidt, R.; Van Lunzen, J.; Degen, O.; Stellbrink, H.J.; Staszewski, S.; Bogner, J.; Fatkenheuer, G.; Kosmidis, J.; Gargalianos, P.; Xylomenos, G.; Perdios, J.; Panos, G.; Filandras, A.; Karabatsaki, E.; Sambatakou, H.; Banhegyi, D.; Mulcahy, F.; Yust, I.; Turner, D.; Burke, M.; Pollack, S.; Hassoun, G.; Maayan, S.; Vella, S.; Esposito, R.; Mazeu, I.; Mussini, C.; Arici, C.; Pristera, R.; Mazzotta, F.; Gabbuti, A.; Vullo, V.; Lichtner, M.; Chirianni, A.; Montesarchio, E.; Gargiulo, M.; Antonucci, G.; Iacomi, F.; Narciso, P.; Vlassi, C.; Zaccarelli, M.; Lazzarin, A.; Finazzi, R.; Galli, M.; Ridolfo, A.; D'Arminio Monforte, A.; Rozentale, B.; Aldins, P.; Chaplinskas, S.; Hemmer, R.; Staub, T.; Reiss, P.; Ormaasen, V.; Maeland, A.; Brunn, J.; Knysz, B.; Gasiorowski, J.; Horban, A.; Bakowska, E.; Prokopowicz, D.; Flisiak, R.; Boron-Kaczmarska, A.; Pynka, M.; Beniowski, M.; Mularska, E.; Trocha, H.; Jablonowska, E.; Malolepsza, E.; Wojcik, K.; Antunes, F.; Valadas, E.; Mansinho, K.; Maltez, F.; Duiculescu, D.; Rakhmanova, A.; Vinogradova, E.; Buzunova, S.; Jevtovic, D.; Mokras, M.; Stanekova, D.; Tomazic, J.; Gonzalez-Lahoz, J.; Soriano, V.; Martin-Carbonero, L.; Labarga, P.; Moreno, S.; Clotet, B.; Jou, A.; Paredes, R.; Tural, C.; Puig, J.; Bravo, I.; Gatell, J.M.; Miro, J.M.; Domingo, P.; Gutierrez, M.; Mateo, G.; Sambeat, M.; Karlsson, A.; Persson, P.O.; Flamholc, L.; Ledergerber, B.; Weber, R.; Francioli, P.; Cavassini, M.; Hirschel, B.; Boffi, E.; Furrer, H.; Battegay, M.; Elzi, L.; Kravchenko, E.; Chentsova, N.; Kutsyna, G.; Servitskiy, S.; Krasnov, M.; Barton, S.; Johnson, A.M.; Mercey, D.; Phillips, A.; Johnson, M.A.; Mocroft, A.; Murphy, M.; Weber, J.; Scullard, G.; Fisher, M.; Leen, C.; Gatell, J.; Gazzard, B.; Lundgren, J.; Kirk, O.; Cozzi-Lepri, A.; Grint, D.; Ellefson, M.; Podlekareva, D.; Kjaer, J.; Peters, L.; Reekie, J.; Kowalska, J.; Tverland, J.; Fischer, A.H.

doi:10.1093/infdis/jir385

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.

A376s in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy / R. Paredes, M.C. Puertas, W. Bannister, M. Kisic, A. Cozzi-Lepri, C. Pou, R. Bellido, G. Betancor, J. Bogner, P. Gargalianos, D. Banhegyi, B. Clotet, J. Lundgren, L. Menendez-Arias, J. Martinez-Picado, 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.-.E. Hansen, P. Skinhoj, C. Pedersen, L. Oestergaard, K. Zilmer, J. Smidt, M. Ristola, C. Katlama, J.-. Viard, P.-. 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, J. Bogner, G. Fatkenheuer, 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 Monforte, 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. Mokras, D. Stanekova, J. Tomazic, J. Gonzalez-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. Miro, P. Domingo, M. Gutierrez, G. Mateo, M. Sambeat, A. Karlsson, P.O. Persson, L. Flamholc, 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, A. Mocroft, M. Murphy, J. Weber, G. Scullard, M. Fisher, C. Leen, J. Gatell, B. Gazzard, J. Lundgren, O. Kirk, A. Cozzi-Lepri, D. Grint, M. Ellefson, D. Podlekareva, J. Kjaer, L. Peters, J. Reekie, J. Kowalska, J. Tverland, A.H. Fischer. - In: THE JOURNAL OF INFECTIOUS DISEASES. - ISSN 0022-1899. - 204:5(2011 Sep 01), pp. 741-752. [10.1093/infdis/jir385]

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

Paredes R.;Puertas M. C.;Bannister W.;Kisic M.;Cozzi-Lepri A.;Pou C.;Bellido R.;Betancor G.;Bogner J.;Gargalianos P.;Banhegyi D.;Clotet B.;Lundgren J.;Menendez-Arias L.;Martinez-Picado J.;Losso M.;Elias C.;Vetter N.;Zangerle R.;Karpov I.;Vassilenko A.;Mitsura V. M.;Suetnov O.;Clumeck N.;De Wit S.;Poll B.;Colebunders R.;Vandekerckhove L.;Hadziosmanovic V.;Kostov K.;Begovac J.;Machala L.;Rozsypal H.;Sedlacek D.;Nielsen J.;Kronborg G.;Benfield T.;Larsen M.;Gerstoft J.;Katzenstein T.;Hansen A. -B. E.;Skinhoj P.;Pedersen C.;Oestergaard L.;Zilmer K.;Smidt J.;Ristola M.;Katlama C.;Viard J. -P.;Girard P. -M.;Livrozet J. M.;Vanhems P.;Pradier C.;Dabis F.;Neau D.;Rockstroh J.;Schmidt R.;Van Lunzen J.;Degen O.;Stellbrink H. J.;Staszewski S.;Bogner J.;Fatkenheuer G.;Kosmidis J.;Gargalianos P.;Xylomenos G.;Perdios J.;Panos G.;Filandras A.;Karabatsaki E.;Sambatakou H.;Banhegyi D.;Mulcahy F.;Yust I.;Turner D.;Burke M.;Pollack S.;Hassoun G.;Maayan S.;Vella S.;Esposito R.;Mazeu I.;Mussini C.;Arici C.;Pristera R.;Mazzotta F.;Gabbuti A.;Vullo V.;Lichtner M.;Chirianni A.;Montesarchio E.;Gargiulo M.;Antonucci G.;Iacomi F.;Narciso P.;Vlassi C.;Zaccarelli M.;Lazzarin A.;Finazzi R.;M. Galli;Ridolfo A.;A. D'Arminio Monforte;Rozentale B.;Aldins P.;Chaplinskas S.;Hemmer R.;Staub T.;Reiss P.;Ormaasen V.;Maeland A.;Brunn J.;Knysz B.;Gasiorowski J.;Horban A.;Bakowska E.;Prokopowicz D.;Flisiak R.;Boron-Kaczmarska A.;Pynka M.;Beniowski M.;Mularska E.;Trocha H.;Jablonowska E.;Malolepsza E.;Wojcik K.;Antunes F.;Valadas E.;Mansinho K.;Maltez F.;Duiculescu D.;Rakhmanova A.;Vinogradova E.;Buzunova S.;Jevtovic D.;Mokras M.;Stanekova D.;Tomazic J.;Gonzalez-Lahoz J.;Soriano V.;Martin-Carbonero L.;Labarga P.;Moreno S.;Clotet B.;Jou A.;Paredes R.;Tural C.;Puig J.;Bravo I.;Gatell J. M.;Miro J. M.;Domingo P.;Gutierrez M.;Mateo G.;Sambeat Ma.;Karlsson A.;Persson P. O.;Flamholc L.;Ledergerber B.;Weber R.;Francioli P.;Cavassini M.;Hirschel B.;Boffi E.;Furrer H.;Battegay M.;Elzi L.;Kravchenko E.;Chentsova N.;Kutsyna G.;Servitskiy S.;Krasnov M.;Barton S.;Johnson A. M.;Mercey D.;Phillips A.;Johnson M. A.;Mocroft A.;Murphy M.;Weber J.;Scullard G.;Fisher M.;Leen C.;Gatell J.;Gazzard B.;Lundgren J.;Kirk O.;Cozzi-Lepri A.;Grint D.;Ellefson M.;Podlekareva D.;Kjaer J.;Peters L.;Reekie J.;Kowalska J.;Tverland J.;Fischer A. H.

2011

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 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.

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	Parole chiave
	
			Adult; Benzoxazines; Drug Resistance, Viral; Female; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Male; Middle Aged; Models, Molecular; Mutation; Nevirapine; Protein Structure, Tertiary; Reverse Transcriptase Inhibitors; Risk Factors; Treatment Failure; Viral Load
		
	Settori scientifico-disciplinari dell'articolo
	
			Settore MED/17 - Malattie Infettive
		
	Data di pubblicazione
	
			1-set-2011
		
	Rivista in ANCE
	
			THE JOURNAL OF INFECTIOUS DISEASES
		
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			https://dx.doi.org/10.1093/infdis/jir385
		
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			01 - Articolo su periodico

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