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N348I in HIV-1 Reverse Transcriptase Counteracts the Synergy Between Zidovudine and Nevirapine

Yap, Soo Huey BSc (Hons)*,†; Herman, Brian D. PhD; Radzio, Jessica PhD; Sluis-Cremer, Nicolas PhD; Tachedjian, Gilda PhD*,§,‖

JAIDS Journal of Acquired Immune Deficiency Syndromes: October 1st, 2012 - Volume 61 - Issue 2 - p 153–157
doi: 10.1097/QAI.0b013e3182657990
Brief Report: Basic and Translational Science

Abstract: The efficacy of regimens that include both zidovudine and nevirapine can be explained by the synergistic interactions between these drugs. N348I in HIV-1 reverse transcriptase confers decreased susceptibility to zidovudine and nevirapine. Here, we demonstrate that N348I reverses the synergistic inhibition of HIV-1 by zidovudine and nevirapine. Also, the efficiency of zidovudine-monophosphate excision in the presence of nevirapine is greater for N348I HIV-1 reverse transcriptase compared with the wild-type enzyme. These data help explain the frequent selection of N348I in regimens that contain zidovudine and nevirapine, and suggest that the selection of N348I should be monitored in resource-limited settings where these drugs are routinely used.

*Retroviral Biology and Antivirals Laboratory, Centre for Virology, Burnet Institute, Melbourne, Victoria, Australia

School of Applied Sciences and Engineering, Monash University, Churchill, Victoria, Australia

Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA

Departments of §Microbiology

Medicine, Monash University, Melbourne, Clayton, Victoria, Australia.

Correspondence to: Gilda Tachedjian, PhD, Retroviral Biology and Antivirals Laboratory, Centre for Virology, Burnet Institute, GPO Box 2284, Melbourne, Victoria, 3001, Australia (e-mail: gildat@burnet.edu.au).

Presented previously at the 15th Conference on Retroviruses and Opportunistic Infections, February 3–6, 2008, Boston and published as Abstract #79 in S. H. Yap, J. Radzio, N. Sluis-Cremer, G. Tachedjian. Mechanism by which N348I in HIV-1 reverse transcriptase confers dual zidovudine/nevirapine resistance.

Supported by the National Health and Medical Research Council of Australia (NHMRC) Senior Research Fellowship 543105 and NHMRC Project Grants 433903 and 603704 (to G. Tachedjian); by the United States National Institutes of Health Grant R01 AI081571 (to N. Sluis-Cremer); by the Monash University Postgraduate Award (to S. H. Yap); NIH T32 training Grant AI-49820-9 (to B. D. Herman). The authors gratefully acknowledge the contribution to this work of the Victorian Operational Infrastructure Support Program received by the Burnet Institute.

The authors have no conflicts of interest to disclose.

Received August 28, 2011

Accepted June 19, 2012

© 2012 by Lippincott Williams & Wilkins