Lars Jørgen Østergaard

A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Roger Paredes
  • ,
  • Maria Carmen Puertas, Unknown
  • Wendy Bannister, Unknown
  • Mónica Kisic, Unknown
  • Alessandro Cozzi-Lepri
  • ,
  • Christian Pou, Unknown
  • Rocío Bellido, Unknown
  • Gilberto Betancor, Unknown
  • Johannes Bogner, Unknown
  • Panagiotis Gargalianos, Unknown
  • Dénes Bánhegyi
  • ,
  • Bonaventura Clotet
  • ,
  • Jens Lundgren
  • ,
  • Luis Menéndez-Arias, Unknown
  • Javier Martinez-Picado, Unknown
  • EuroSIDA Study Group (Lars Østergaard, member)

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.

Original languageEnglish
JournalJournal of Infectious Diseases
Volume204
Issue5
Pages (from-to)741-52
Number of pages12
ISSN0022-1899
DOIs
Publication statusPublished - 1 Sep 2011

    Research areas

  • 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

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