Help From Herpes? Coinfection Induces Acyclovir To Inhibit HIV

Commonly, individuals infected with HIV are infected also with other microbes. Infection with human herpesvirus (HHV), especially with herpes simplex virus-2 (HSV-2), is often associated with HIV. These HHV infections may be either active or dormant, but HIV infection makes HHV reactivation more likely.

For many years, acyclovir (ACV), a well-studied drug, has been used safely to treat HHV in humans. "HHV has a unique ability to phosphorylate ACV to activate it, making the drug quite specific for HHV and, for the same reason, relatively non-active against other viruses, including HIV," offers senior study author Dr. Leonid Margolis from the National Institute of Health. Nevertheless, some patients coinfected with HIV and HSV-2 exhibit lower HIV levels after ACV treatment.

"We decided to investigate this phenomenon experimentally using small blocks of human tissues" says Dr. Margolis. "Drs. Andrea Lisco and Christophe Vanpouille who performed this work in my laboratory found that although ACV doesn't inhibit HIV in 'sterile' cell lines, it does, surprisingly, suppress HIV in tissues that carry no HSV-2 but various other HHVs." In collaboration with a prominent AIDS researcher Dr. Raymond Schinazi from Emory University and Dr. Matthias Gotte from McGill University, the researchers found that phosphorylated ACV that is formed in HHV-infected cells directly inhibits the HIV-1 reverse transcriptase (RT), thus preventing HIV from copying itself.

These results not only help to explain the response to ACV seen in patients coinfected with HSV-2 and HIV, but also suggest that ACV may be used against HIV in patients infected with various other HHVs, including the low-pathogenic and ubiquitous HHV-6 and HHV-7. Moreover, in collaboration with Drs. Balzarini from Catholic University of Leuven and McGuigan from Cardiff University, Dr. Margolis and his team demonstrated that new strategies for development of novel HIV inhibitors based on ACV structure can now be developed. "We provide definitive experimental evidence of inhibition of HIV-1 RT activity by phosphorylated ACV and demonstrate that ACV phosphorylation occurring in human tissues infected by various HHVs transforms this widely-used inexpensive anti-herpes drug into a direct HIV inhibitor," concludes Dr. Margolis.

The researchers include Andrea Lisco, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; Christophe Vanpouille, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; Egor P. Tchesnokov, McGill University, Montreal, Quebec, Canada; Jean-Charles Grivel, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; Angelique Biancotto, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; Beda Brichacek, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; Julie Elliott, UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, CA; Emilie Fromentin, Emory University School of Medicine, Decatur, GA; Robin Shattock, St. George's University of London, London, UK; Peter Anton, UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, CA; Robert Gorelick, AIDS Vaccine Program SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD; Jan Balzarini, Rega Institute for Medical Research, Katholieke Universiteit, Leuven, Belgium; Christopher McGuigan, Welsh School of Pharmacy, Cardiff University, Cardiff, UK; Marco Derudas, Welsh School of Pharmacy, Cardiff University, Cardiff, UK; Matthias Gotte, McGill University, Montreal, Quebec, Canada; Raymond F. Schinazi, Emory University School of Medicine, Decatur, GA; and Leonid Margolis, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.