Selective Excision of AZTMP by Drug-Resistant Human Immunodeficiency Virus Reverse Transcriptase

doi:10.1128/JVI.75.10.4832-4842.2001

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Journal of Virology, May 2001, p. 4832-4842, Vol. 75, No. 10
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.10.4832-4842.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Selective Excision of AZTMP by Drug-Resistant Human Immunodeficiency Virus Reverse Transcriptase

Paul L. Boyer,¹ Stefan G. Sarafianos,² Edward Arnold,² and Stephen H. Hughes¹^,^*

ABL Basic Research Program, National Cancer Institute Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201,¹ and Center for Advanced Biotechnology and Medicine and Chemistry Department, Rutgers University, Piscataway, New Jersey 08854-5638²

Received 10 November 2000/Accepted 19 February 2001

Two distinct mechanisms can be envisioned for resistance of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase(RT) to nucleoside analogs: one in which the mutations interferewith the ability of HIV-1 RT to incorporate the analog, and theother in which the mutations enhance the excision of the analogafter it has been incorporated. It has been clear for some timethat there are mutations that selectively interfere with the incorporationof nucleoside analogs; however, it has only recently been proposedthat zidovudine (AZT) resistance can involve the excision of thenucleoside analog after it has been incorporated into viral DNA.Although this proposal resolves some important issues, it leavessome questions unanswered. In particular, how do the AZT resistancemutations enhance excision, and what mechanism(s) causes the excisionreaction to be relatively specific for AZT? We have used bothstructural and biochemical data to develop a model. In this model,several of the mutations associated with AZT resistance act primarilyto enhance the binding of ATP, which is the most likely pyrophosphatedonor in the in vivo excision reaction. The AZT resistance mutationsserve to increase the affinity of RT for ATP so that, at physiologicalATP concentrations, excision is reasonably efficient. So far aswe can determine, the specificity of the excision reaction foran AZT-terminated primer is not due to the mutations that conferresistance, but depends instead on the structure of the regionaround the HIV-1 RT polymerase active site and on its interactionswith the azido group of AZT. Steric constraints involving theazido group cause the end of an AZT 5'-monophosphate-terminatedprimer to preferentially reside at the nucleotide binding site,which favorsexcision.

^* Corresponding author. Mailing address: HIV Drug Resistance Program, National Cancer Institute-FCRDC, P.O. Box B, Building539, Room 130A, Frederick, MD 21702-1201. Phone: (301) 846-1619.Fax: (301) 846-6966. E-mail: hughes{at}ncifcrf.gov.

Journal of Virology, May 2001, p. 4832-4842, Vol. 75, No. 10
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.10.4832-4842.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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