1. A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy
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Adriano LAZZARIN, MASSIMO GALLI, Wendy Bannister, Emília Valadas, Robert Flisiak, Francisco Antunes, Renato Alberto Finazzi, Jens Lundgren, Dalibor Sedlacek, LUZ MARTÍN CARBONERO, Clifford Leen, Vicente Soriano, Luis Menendez Arias, Linos Vandekerckhove, Matti Ristola, Lars Østergaard, Đorđe Jevtović, Justyna Kowalska, Thomas Benfield, Viktar M. Mitsura, Terese L Katzenstein, Gilberto Betancor Quintana, Vassilenko Anna, Maria C. Puertas, Miriam Lichtner, Javier Martinez-Picado, Amsterdam institute for Infection and Immunity, Amsterdam Public Health, and Global Health
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Cyclopropanes ,Models, Molecular ,Male ,Drug Resistance ,HIV Infections ,Drug resistance ,chemistry.chemical_compound ,Models ,Risk Factors ,Immunology and Allergy ,Medicine ,Viral ,Treatment Failure ,0303 health sciences ,biology ,Benzoxazines/pharmacology/therapeutic use ,Viral/ genetics ,Female ,Genotype ,HIV Infections/ drug therapy/virology ,HIV Reverse Transcriptase/ genetics ,HIV-1/drug effects/enzymology/ genetics ,Humans ,Middle Aged ,Molecular ,Mutation ,Nevirapine/pharmacology/ therapeutic use ,Protein Structure ,Tertiary ,Reverse Transcriptase Inhibitors/pharmacology/ therapeutic use ,Viral Load ,virus diseases ,HIV Reverse Transcriptase ,3. Good health ,Infectious Diseases ,Alkynes ,Reverse Transcriptase Inhibitors ,Viral load ,medicine.drug ,Adult ,Efavirenz ,Nevirapine ,RNase P ,macromolecular substances ,03 medical and health sciences ,Zidovudine ,Drug Resistance, Viral ,Benzoxazines ,HIV-1 ,Protein Structure, Tertiary ,RNase H ,030304 developmental biology ,030306 microbiology ,business.industry ,Virology ,Reverse transcriptase ,chemistry ,biology.protein ,business - 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.
- Published
- 2011
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