News Release: Research , School of Medicine

Sep. 10,  2008

Herpes Drug Acyclovir Also Suppresses HIV in Herpes-Infected Tissue

The drug acyclovir, used successfully for decades to suppress outbreaks of oral and genital herpes, also can directly suppress HIV-1 in tissues already infected with a herpesvirus, researchers have discovered. The finding opens the way for the development of a new type of anti-HIV drug based on acyclovir.

The research is published online by the journal "Cell Host & Microbe." The international research team included scientists from Emory University, the Atlanta Veterans Affairs Medical Center, the National Institute of Child Health and Human Development (NICHD), McGill University, Leuven University and Cardiff University.

Herpes simplex virus 2 (HSV-2), which causes genital herpes, is often found in HIV-1 infected persons. HSV-2 has been found to increase HIV-1 transmission and a worse clinical outcome in those who are co-infected.

Although researchers previously have found that acyclovir can suppress HIV-1 in those co-infected with herpesviruses, until now this effect was believed to be an indirect result of suppressing the inflammation caused by herpes. The current study, however, shows that acyclovir has a direct effect on suppressing HIV-1 in tissue that is co-infected with several herpesviruses, not necessarily HSV-2.

When acyclovir is given to persons infected with herpesviruses, it is selectively activated through a viral-induced process called phosphorylation, in which a viral enzyme adds a chemical group containing phosphorous. The activated form of acyclovir, called acyclovir triphosphate, is very effective in suppressing herpesviruses. The research team, using human tonsil as well as other tissues, discovered that this same chemical process activates acyclovir to directly inhibit the HIV-1 reverse transcriptase, which is necessary for HIV-1 to translate its genetic information from HIV RNA into viral DNA and to reproduce.

The researchers also discovered that acyclovir was not effective in suppressing HIV-1 in tissues that were not infected with herpesviruses or in herpesvirus-free cell cultures. When they added herpesvirus-infected cells to these cultures, however, acyclovir was activated to suppress HIV-1.

The researchers also found that if they provided a "prodrug" version of pre-phosphorylated acyclovir to HIV-infected tissue it also suppressed HIV, bypassing the need for activation by a herpesvirus.

Although herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2) are the most well known of these viruses, several of the most widespread herpesviruses are benign and asymptomatic and are harbored by most people. Now, the researchers showed that these widespread herpesviruses also can activate acyclovir into a HIV-1 inhibitor and acyclovir suppresses HIV in human tissues coinfected with these viruses.

"This discovery by our International collaborative research team that activated acyclovir can suppress HIV paves the way for additional research on the possible uses of this drug and holds promise for the development of new treatments, combining acyclovir with other antiretroviral therapies," says Raymond Schinazi, PhD, DSc, professor of pediatrics at Emory University School of Medicine and senior research career scientist at the Atlanta Veterans Affairs Medical Center.

The study's senior author was Leonid Margolis, PhD, head of NICHD's Section on Intercellular Interactions. Co-first authors were Andrea Lisco and Christophe Vanpouille from the NICHD.

Reference: Lisco et al., Acyclovir Is Activated into a HIV-1 Reverse Transcriptase Inhibitor in Herpesvirus-Infected Human Tissues, Cell Host & Microbe (2008), doi:10.1016/j.chom.2008.07.008.

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