A team of researchers has identified how the anti-herpes drug acyclovir (Zovirax) limits HIV replication in people coinfected with herpes simplex virus (HSV), according to a report published in the September 11 issue of Cell Host & Microbe.
During the past 15 years, scientists have occasionally reported that people with HIV taking acyclovir for herpes also appear to have survival advantages and reductions in HIV levels, compared with people coinfected with both viruses not taking acyclovir. Until now, however, researchers doubted that acyclovir directly affected HIV replication. Rather, because acyclovir can reduce inflammation of the immune system by lowering herpes virus levels, experts assumed it also reduces the number active CD4 cells that can become targets of HIV infection.
Andrea Lisco, MD, PhD, from the National Institutes of Health in Bethesda, Maryland, and her colleagues suspected that acyclovir may actually have direct anti-HIV activity, at least within cells that are also infected with herpes viruses. Their suspicions were due to the way that acyclovir works.
For acyclovir to be incorporated into newly forming herpes viruses—thus stopping viral replication—it must first bind to phosphorus molecules with the help of a herpes virus enzyme called thymidine kinase. Dr. Lisco and her team theorized that acyclovir may act against HIV only once it has been bound to phosphorus molecules, a process called phosphorylation, which can only occur in herpes infected cells carrying the thymidine kinase enzyme.
Lisco’s team first studied acyclovir’s impact on HIV in cells that were infected or uninfected with herpes. They confirmed that HIV reproduction did decrease only in cells infected with herpes. Taking their experiments one step further, they added a laboratory version of acyclovir that was already phosphorylated. The phosphorylated acyclovir acted against HIV even in cells that weren’t coinfected with herpes.
The authors suggest that treating people infected with both HIV and herpes with both HIV treatments and acyclovir could diminish the likelihood of transmitting HIV—a conclusion that has been offered by other research teams. They also comment that further research should be conducted with various formulations of acyclovir to determine whether it may have a role in combination anti-HIV therapy.
Acyclovir Is Activated into a HIV-1 Reverse Transcriptase Inhibitor in Herpesvirus-Infected Human Tissues
For most viruses, there is a need for antimicrobials that target unique viral molecular properties. Acyclovir (ACV) is one such drug. It is activated into a human herpesvirus (HHV) DNA polymerase inhibitor exclusively by HHV kinases and, thus, does not suppress other viruses. Here, we show that ACV suppresses HIV-1 in HHV-coinfected human tissues, but not in HHV-free tissue or cell cultures.
However, addition of HHV-6-infected cells renders these cultures sensitive to anti-HIV ACV activity. We hypothesized that such HIV suppression requires ACV phosphorylation by HHV kinases. Indeed, an ACV monophosphorylated prodrug bypasses the HHV requirement for HIV suppression. Furthermore, phosphorylated ACV directly inhibits HIV-1 reverse transcriptase (RT), terminating DNA chain elongation, and can trap RT at the termination site. These data suggest that ACV anti-HIV-1 activity may contribute to the response of HIV/HHV-coinfected patients to ACV treatment and could guide strategies for the development of new HIV-1 RT inhibitors.
Andrea Lisco, Christophe Vanpouille, Egor P. Tchesnokov, Jean-Charles Grivel, Ange’lique Biancotto, Beda Brichacek, Julie Elliott, Emilie Fromentin, Robin Shattock, Peter Anton, Robert Gorelick, Jan Balzarini, Christopher McGuigan, Marco Derudas, Matthias Gotte, Raymond F. Schinazi and Leonid Margolis
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
Department of Microbiology and Immunology, McGill University, Montreal, Que’bec H3A 2B4, Canada
Center for Prevention Research, UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1678, USA
Veterans Affairs Medical Center, Emory University School of Medicine, Decatur, GA 30033-4501, USA
St. George’s University of London, London, SW17 0RE, UK
AIDS Vaccine Program SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD 21702, USA
Rega Institute for Medical Research, Katholieke Universiteit, B-3000 Leuven, Belgium
Welsh School of Pharmacy, Cardiff University, Cardiff, CF10 3NB, UK