The M184V Mutation in the Reverse Transcriptase of Human Immunodeficiency Virus Type 1 Impairs Rescue of Chain-Terminated DNA Synthesis

doi:10.1128/JVI.74.8.3579-3585.2000

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Journal of Virology, April 2000, p. 3579-3585, Vol. 74, No. 8
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The M184V Mutation in the Reverse Transcriptase of Human Immunodeficiency Virus Type 1 Impairs Rescue of Chain-Terminated DNA Synthesis

Matthias Götte,¹ Dominique Arion,¹ Michael A. Parniak,¹ and Mark A. Wainberg¹^,²^,^*

McGill University AIDS Centre, Lady Davis Institute-Jewish General Hospital,¹ and Department of Microbiology and Immunology, McGill University,² Montréal, Québec, Canada

Received 29 September 1999/Accepted 25 January 2000

Nucleoside analog chain terminators such as 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxy-3'-thiacytidine (3TC) representan important class of drugs that are used in the clinic to inhibitthe reverse transcriptase (RT) of human immunodeficiency virustype 1. Recent data have suggested that mutant enzymes associatedwith AZT resistance are capable of removing the chain-terminatingresidue with much greater efficiency than wild-type RT and thismay, in turn, facilitate rescue of DNA synthesis; these experimentswere performed using physiological concentrations of pyrophosphateor nucleoside triphosphates, respectively. The present study demonstratesthat the M184V mutation, which confers high-level resistance to3TC, can severely compromise the removal of chain-terminatingnucleotides. Pyrophosphorolysis on 3TC-terminated primer strandswas not detectable with M184V-containing, as opposed to wild-type,RT, and rescue of AZT-terminated DNA synthesis was significantlydecreased with the former enzyme. Thus, mutated RTs associatedwith resistance to AZT and 3TC possess opposing, and thereforeincompatible, phenotypes in this regard. These results are consistentwith tissue culture and clinical data showing sustained antiviraleffects of AZT in the context of viruses that contain the M184Vmutation in the RT-encodinggene.

^* Corresponding author. Mailing address: McGill AIDS Centre, Lady Davis Institute-Jewish General Hospital, 3755 Chemin Côte-Ste-Catherine,Montréal, Québec, Canada H3T 1E2. Phone: (514) 340-7536. Fax:(514) 340-7537. E-mail: mdwa{at}musica.mcgill.ca.

Journal of Virology, April 2000, p. 3579-3585, Vol. 74, No. 8
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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