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J. Biol. Chem., Vol. 283, Issue 46, 31289-31293, November 14, 2008

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The Antiherpetic Drug Acyclovir Inhibits HIV Replication and Selects the V75I Reverse Transcriptase Multidrug Resistance Mutation^*

Moira A. McMahon, Janet D. Siliciano, Jun Lai^¶, Jun O. Liu, James T. Stivers, Robert F. Siliciano^¶, and Rahul M. Kohli¹

From the Department of Pharmacology and Molecular Sciences and the Department of Medicine, Johns Hopkins University School of Medicine, Baltimore Maryland 21205 and the ^¶Howard Hughes Medical Institute, Baltimore Maryland 21205

The antiviral drug acyclovir is a guanosine nucleoside analog that potently inhibits herpes simplex virus (HSV) replication. Acyclovir treatment in patients coinfected with HSV and human immunodeficiency virus (HIV) has been observed to alter disease course and decrease HIV viral load, a finding that has been attributed to indirect effects of HSV suppression on HIV replication. Based on this hypothesis, several clinical studies have recently investigated the use of acyclovir for treatment of patients coinfected with HSV and HIV or for prophylaxis against HIV transmission. In this report, we use a single round HIV infectivity assay to show that acyclovir directly inhibits HIV infection with an IC₅₀ of 5 µM. The target of acyclovir in HIV-infected cells is validated as HIV reverse transcriptase (RT) by the emergence of the RT variant V75I under the selective pressure of acyclovir. The V75I mutation is part of the multidrug resistance pathway that enhances viral resistance to many of the best RT inhibitors approved for the treatment of HIV. Biochemical analyses demonstrate that acyclovir triphosphate is a chain terminator substrate for HIV RT and can compete with dGTP for incorporation into DNA. Although acyclovir may prove a useful lead for development of new HIV treatments, the selection of resistant mutants raises a cautionary note to the use of acyclovir monotherapy in patients coinfected with HSV and HIV.

Received for publication, September 19, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grants AI43222 (to R. F. S.) and GM56834-12 (to J. T. S.). 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.

¹ To whom correspondence should be addressed: Division of Infectious Diseases, Dept. of Medicine, Johns Hopkins University School of Medicine, 1830 Monument St., Baltimore MD 21205. Tel.: 410-614-9644; Fax: 410-955-3023; E-mail: rkohli2{at}jhmi.edu.

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