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J. Biol. Chem., Vol. 278, Issue 36, 34403-34410, September 5, 2003

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Mutations E44D and V118I in the Reverse Transcriptase of HIV-1 Play Distinct Mechanistic Roles in Dual Resistance to AZT and 3TC^*

Mélanie Girouard  , Karidia Diallo  , Bruno Marchand  , Suzanne McCormick  and Matthias Götte   ¶ ||

From the McGill University AIDS Centre, Lady Davis Institute-Jewish General Hospital, and the Departments of Microbiology and Immunology and ^¶Medicine, McGill University, Montréal, Québec H3T 1E2, Canada

Retroviral resistance to AZT and 3TC has been associated with two different mechanisms. The M184V mutation in the reverse transcriptase (RT) of the human immunodeficiency virus, type 1 (HIV-1) diminishes the incorporation of 3TC-monophosphate (3TC-MP), whereas AZT resistance-conferring mutations were shown to facilitate the phosphorolytic excision of incorporated AZT-MP in the presence of ATP. Both mechanisms show a certain degree of incompatibility; however, previous clinical data revealed that mutations E44D and V118I, when present in a background of classical AZT mutations (M41L, D67N, L210W, and T215Y), confer dual resistance to AZT and 3TC. We have purified RT enzymes that contain E44D and V118I either alone or in a background of different combinations of AZT mutations to study the underlying biochemical mechanisms. We found that enzymes containing E44D in a background of these latter mutations increase the efficiency of excision of 3TC-MP. Unexpectedly, V118I-containing enzymes show dramatic reductions in rates of incorporation of AZT-MP and 3TC-MP. The V118I mutant is also associated with diminished rates of ATP-dependent primer unblocking. The additional presence of mutations M41L, D67N, L210W, and T215Y can partially neutralize this deficit, which helps to explain the concurrent presence of these changes in resistant isolates. These biochemical data make clear that mutations E44D and V118I play distinct mechanistic roles in dual resistance to AZT and 3TC. Our findings are consistent with an increasing number of clinical studies suggesting that the V118I cluster constitutes a novel pathway for HIV resistance to multiple nucleotide analogue RT inhibitors.

Received for publication, April 4, 2003 , and in revised form, June 19, 2003.

^* This work was supported in part by grants from the Canadian Institutes of Health Research and le Ministère de la Recherche, de la Science et de la Technologie du Québec (to M. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: McGill University AIDS Centre (226), Lady Davis Institute-Jewish General Hospital, 3755, chemin Côte-Ste-Catherine, Montréal, Québec H3T 1E2, Canada. Tel.: 514-340-8222 (ext. 3299); Fax: 514-340-7502; E-mail: mgoette{at}ldi.jgh.mcgill.ca.

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