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 the National Institutes of Health (Eunice Kennedy Shriver National Institute of Child Health and Human Development), Emory University, the Atlanta Veterans Affairs Medical Center, McGill Leuven University and Cardiff University, along with other colleagues.
Herpes simplex virus 2 (HSV-2), which causes genital herpes, often is associated with HIV-1 and has been found to cause an increase in 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 acyclovir 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 a herpesvirus.
When acyclovir is given to patients with herpesviruses, it is activated through a chemical process called phosphorylation, in which viral enzymes add a chemical group containing phosphorous. This activated form of acyclovir is very effective in suppressing herpesviruses. The research team, using human tonsil tissue, discovered that this same chemical process activates acyclovir to directly inhibit the HIV-1 reverse transcriptase, which is necessary for the HIV-1 virus 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 in tissue that was not infected with some type of herpesvirus. When they added herpesvirus-infected cells to these tissue cultures, however, acyclovir was activated to suppress HIV.
The researchers also found that if they provided a "prodrug" version of pre-phosphorylated acyclovir to HIV-infected tissue it also suppresses HIV, bypassing the need for activation via 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.
"This discovery by our 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, MD, 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: "Acyclovir Is Activated into a HIV-1 Reverse Transcriptase Inhibitor in Herpesvirus-Infected Human Tissues." A. Lisco, C. Vanpouille, E. P. Tchesnokov, J.-C. Grivel, A. Biancotto, B. Brichacek, J. Elliott, E. Froentin, R. Shattock, P. Anton, R. Gorelick, J. Balzarini, C. McGuigan, M. Derudas, M. Gotte, R. F. Schinazi, and L. Margolis. Cell Host & Microbe 4, 1-11, September 11, 2008.