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J Biol Chem, Vol. 275, Issue 13, 9251-9255, March 31, 2000
From the Lady Davis Institute for Medical Research and McGill
University AIDS Centre, Sir Mortimer B. Davis-Jewish General
Hospital, Montreal, Quebec H3T 1E2, Canada
The development of phosphonoformic acid (PFA)
resistance against a background of 3'-azido-3'-deoxythymidine (AZT)
resistance in human immunodeficiency virus type 1 (HIV-1) restores
viral sensitivity to AZT. High level AZT resistance requires multiple mutations (D67N/K70R/T215F/K219Q). In order to characterize the mechanism of PFA resistance-mediated resensitization to AZT, the A114S
mutation associated with PFA resistance was introduced into the reverse
transcriptase (RT) of both wild type and drug-resistant virus. We
previously showed that pyrophosphorolytic removal of chain-terminating
AZT is the primary mechanism of the AZT resistance phenotype (Arion,
D., Kaushik, N., McCormick, S., Borkow, G., and Parniak, M. A. (1998) Biochemistry 37, 15908-15917). Introduction of
A114S into the AZT resistance background significantly diminishes both
the enhanced pyrophosphorolytic activity and the DNA synthesis processivity associated with the AZT-resistant RT. The A114S mutation also alters the nucleotide-dependent phosphorolysis activity
associated with AZT resistance. The presence of the A114S mutation
therefore severely impairs the mutant enzyme's ability to excise
chain-terminating AZT. The decrease in phosphorolytic activity of RT
conferred by the PFA resistance A114S mutation resensitizes
AZT-resistant HIV-1 to AZT by allowing the latter to again function as
a chain terminator of viral DNA synthesis. These data further
underscore the importance of phosphorolytic removal of
chain-terminating AZT as the primary mechanism of HIV-1 AZT resistance.
Mechanism by Which Phosphonoformic Acid Resistance Mutations
Restore 3'-Azido-3'-deoxythymidine (AZT) Sensitivity to
AZT-resistant HIV-1 Reverse Transcriptase*
, and
*
This work was supported by Medical Research Council of
Canada (MRCC) Grants GR-13918 and MT-15286 (to M. A. P.) and a grant from the International Research Scholars Program of the Howard Hughes
Medical Institute (to M. A. P.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
An MRCC Postdoctoral Fellow.
§
An MRCC Senior Scientist and an International Research Scholar of
the Howard Hughes Medical Institute. To whom correspondence should be
addressed: Lady Davis Institute for Medical Research and McGill
University AIDS Centre, Sir Mortimer B. Davis-Jewish General Hospital,
3755 Cote Ste-Catherine Rd., Montreal, Quebec H3T 1E2, Canada. Tel.:
514-340-8260; Fax: 514-340-7502; E-mail: mparniak@ldi.jgh.mcgill.ca.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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