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

Paredes, Roger, Puertas, Maria Carmen, Bannister, Wendy, Kisic, Mónica, Cozzi-Lepri, Alessandro, Pou, Christian, Bellido, Rocío, Betancor, Gilberto, Bogner, Johannes, Gargalianos, Panagiotis, Bánhegyi, Dénes, Clotet, Bonaventura, Lundgren, Jens, Menéndez-Arias, Luis, Martinez-Picado, Javier, The EuroSIDA Study Group, and Fisher, Martin (2011) A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy. Journal of Infectious Diseases, 204 (5). pp. 741-752. ISSN 0022-1899

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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.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Brighton and Sussex Medical School
Subjects: R Medicine > RA Public aspects of medicine > RA0421 Public health. Hygiene. Preventive Medicine > RA0643 Communicable diseases and public health > RA0644 Individual diseases or groups of diseases, A-Z > RA0644.A25 AIDS. HIV infections
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Depositing User: Ellen Thomas
Date Deposited: 14 Jan 2014 10:52
Last Modified: 14 Jan 2014 10:52
URI: http://sro.sussex.ac.uk/id/eprint/47289
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