title: A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy.
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.
authors.affiliation: Institut de Recerca de la SIDA--IrsiCaixa, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Paredes
authors.forename: Maria Carmen
authors.initials: MC
authors.lastname: Puertas
authors.forename: Wendy
authors.initials: W
authors.lastname: Bannister
authors.forename: Mónica
authors.initials: M
authors.lastname: Kisic
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cozzi-Lepri
authors.forename: Christian
authors.initials: C
authors.lastname: Pou
authors.forename: Rocío
authors.initials: R
authors.lastname: Bellido
authors.forename: Gilberto
authors.initials: G
authors.lastname: Betancor
authors.forename: Johannes
authors.initials: J
authors.lastname: Bogner
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Gargalianos
authors.forename: Dénes
authors.initials: D
authors.lastname: Bánhegyi
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.forename: Jens
authors.initials: J
authors.lastname: Lundgren
authors.forename: Luis
authors.initials: L
authors.lastname: Menéndez-Arias
authors.forename: Javier
authors.initials: J
authors.lastname: Martinez-Picado
mesh_terms: D000328:Adult; D000480:Alkynes; D048588:Benzoxazines / Q000494:pharmacology / Q000627:therapeutic use; D003521:Cyclopropanes; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D019829:Nevirapine / Q000494:pharmacology / Q000627:therapeutic use*; D017434:Protein Structure, Tertiary; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D012307:Risk Factors; D017211:Treatment Failure; D019562:Viral Load
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; C098320:efavirenz