Exploiting the anti-HIV-1 activity of acyclovir: suppression of primary and drug-resistant HIV isolates and potentiation of the activity by ribavirin.
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.
Eunice Kennedy Shriver National Institute of Child Health and Human Development, Program of Physical Biology, National Institutes of Health, Bethesda, Maryland, USA.
Christophe
C
Vanpouille
Andrea
A
Lisco
Andrea
A
Introini
Jean-Charles
JC
Grivel
Arshi
A
Munawwar
Melanie
M
Merbah
Raymond F
RF
Schinazi
Marco
M
Derudas
Christopher
C
McGuigan
Jan
J
Balzarini
Leonid
L
Margolis
D000212:Acyclovir / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000187:drug effects; D004357:Drug Synergism; D023581:HIV Fusion Inhibitors / Q000494:pharmacology; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D019829:Nevirapine / Q000494:pharmacology; D014066:Palatine Tonsil / Q000187:drug effects* / Q000821:virology; D011480:Protease Inhibitors / Q000494:pharmacology; D012254:Ribavirin / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D046509:Tissue Culture Techniques; D015215:Zidovudine / Q000494:pharmacology
D019380:Anti-HIV Agents; D023581:HIV Fusion Inhibitors; D011480:Protease Inhibitors; D019259:Lamivudine; D012254:Ribavirin; D015215:Zidovudine; D019829:Nevirapine; D000212:Acyclovir