Exploiting the Anti-HIV-1 Activity of Acyclovir: Suppression of Primary and Drug-Resistant HIV Isolates and Potentiation of the Activity by Ribavirin

• Type of Material: Article
• Authors: Christophe Vanpouille, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Andrea Lisco, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Andrea Introini, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Jean-Charles Grivel, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Arshi Munawwar, All India Institute of Medical Sciences; Melanie Merbah, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Raymond Schinazi, Emory University; Marco Derudas, Cardiff University; Christopher McGuigan, Cardiff University; Jan Balzarini, Katholieke Universiteit, Leuven; Leonid Margolis, Eunice Kennedy Shriver National Institute of Child Health and Human Development
• Language: English
• Date: 2012-05-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2012, American Society for Microbiology. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1128/AAC.05986-11
• Title of Journal or Parent Work: Antimicrobial Agents and Chemotherapy
• ISSN: 0066-4804
• Volume: 56
• Issue: 5
• Start Page: 2604
• End Page: 2611
• Grant/Funding Information: Also, this work was supported in part by NIH grant 5P30-AI-50409 (R.F.S.) and by the Department of Veterans Affairs (R.F.S.).; This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and the KU Leuven (GOA no. 10/14).
• Keywords: REVERSE-TRANSCRIPTASE INHIBITOR; DUALLY INFECTED PERSONS; Life Sciences & Biomedicine; HSV SUPPRESSION; PHARMACOLOGY & PHARMACY; HUMAN-IMMUNODEFICIENCY-VIRUS; HEPATITIS-C; THERAPY; MICROBIOLOGY; RNA LEVELS; Microbiology; VALACYCLOVIR; Science & Technology; HERPES-SIMPLEX-VIRUS; Pharmacology & Pharmacy; IN-VIVO
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Microbiology

Abstract

Multiple clinical trials have demonstrated that herpes simplex virus 2 (HSV-2) suppressive therapy using acyclovir (ACV) or valacyclovir in HIV-1/HSV-2-infected persons increased the patient's survival and decreased the HIV-1 load. It has been shown that the incorporation of ACV-monophosphate into the nascent DNA chain instead of dGMP results in the termination of viral DNA elongation and directly inhibits laboratory strains of HIV-1. We evaluated here the anti-HIV activity of ACV against primary HIV-1 isolates of different clades and coreceptor specificity and against viral isolates resistant to currently used drugs, including zidovudine, lamivudine, nevirapine, a combination of nucleoside reverse transcriptase inhibitors (NRTIs), a fusion inhibitor, and two protease inhibitors. We found that, at clinically relevant concentrations, ACV inhibits the replication of these isolates in human tissues infected ex vivo. Moreover, addition of ribavirin, an antiviral capable of depleting the pool of intracellular dGTP, potentiated the ACV-mediated HIV-1 suppression. These data warrant further clinical investigations of the benefits of using inexpensive and safe ACV alone or in combination with other drugs against HIV-1, especially to complement or delay highly active antiretroviral therapy (HAART) initiation in low-resource settings.