Acyclovir is activated into a HIV-1 reverse transcriptase inhibitor in herpesvirus-infected human tissues

• Type of Material: Article
• Authors: Andrea Lisco, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Christophe Vanpouille, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Egor P. Tchesnokov, McGill University; Jean-Charles Grivel, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Angelique Biancotto, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Beda Brichacek, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Julie Elliott, University of California, Los Angeles; Emilie Fromentin, Emory University; Robin Shattock, St. George's University London; Peter Anton, University of California, Los Angeles; Robert Gorelick, NCI-Frederick; Jan Balzarini, Katholieke Universiteit Leuven; Christopher McGuigan, Cardiff University; Marco Derudas, Cardiff University; Matthias Goette, McGill University; Raymond F Schinazi, Emory University; Leonid Margolis, Eunice Kennedy Shriver National Institute of Child Health and Human Development
• Language: English
• Date: 2008-09-11
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2008 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.chom.2008.07.008
• Title of Journal or Parent Work: Cell Host and Microbe
• ISSN: 1931-3128
• Volume: 4
• Issue: 3
• Start Page: 260
• End Page: 270
• Grant/Funding Information: JB is supported by the Geconcerteerde Onderzoeksacties (GOA No. 05/15).; RFS is supported in part by NIH grants 5P30-AI-50409 (CFAR), 5R37-AI-041980 and by the Department of Veterans Affairs.; MG is the recipient of a national career award and a research grant from the Canadian Institutes of Health Research.; This research was supported, in part, by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; and by federal funds from the National Cancer Institute, NIH, under contract NO1-CO-12400.
• Keywords: POLYMERASE TRANSLOCATION; Science & Technology; EX-VIVO; Virology; SUICIDE GENE-THERAPY; IMMUNODEFICIENCY-VIRUS-INFECTION; DOUBLE-BLIND; SIMPLEX-VIRUS; RNA; Microbiology; SUPPRESSION; THYMIDINE KINASE; Parasitology; Life Sciences & Biomedicine; DNA-POLYMERASE
• Research Categories: Biology, Virology; Health Sciences, Pharmacology

Abstract

For most viruses, there is a need for antimicrobials that target unique viral molecular properties. Acyclovir (ACV) is one such drug. It is activated into a human herpesvirus (HHV) DNA polymerase inhibitor exclusively by HHV kinases and, thus, does not suppress other viruses. Here, we show that ACV suppresses HIV-1 in HHV-coinfected human tissues, but not in HHV-free tissue or cell cultures. However, addition of HHV-6-infected cells renders these cultures sensitive to anti-HIV ACV activity. We hypothesized that such HIV suppression requires ACV phosphorylation by HHV kinases. Indeed, an ACV monophosphorylated prodrug bypasses the HHV requirement for HIV suppression. Furthermore, phosphorylated ACV directly inhibits HIV-1 reverse transcriptase (RT), terminating DNA chain elongation, and can trap RT at the termination site. These data suggest that ACV anti-HIV-1 activity may contribute to the response of HIV/HHV-coinfected patients to ACV treatment and could guide strategies for the development of new HIV-1 RT inhibitors.