title: Acyclovir is activated into a HIV-1 reverse transcriptase inhibitor in herpesvirus-infected human tissues.
abstract: 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.
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lisco
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
authors.forename: Christophe
authors.initials: C
authors.lastname: Vanpouille
authors.affiliation: McGill University, Department of Microbiology and Immunology, Montreal, Québec, Canada.
authors.forename: Egor P
authors.initials: EP
authors.lastname: Tchesnokov
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Grivel
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
authors.forename: Angélique
authors.initials: A
authors.lastname: Biancotto
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
authors.forename: Beda
authors.initials: B
authors.lastname: Brichacek
authors.affiliation: Center for Prevention Research, UCLA AIDS Institute, David Geffen School of Medicine at UCLA, CA.
authors.forename: Julie
authors.initials: J
authors.lastname: Elliott
authors.affiliation: Emory University School of Medicine, Veterans Affairs Medical Center, Decatur, GA.
authors.forename: Emilie
authors.initials: E
authors.lastname: Fromentin
authors.affiliation: St. George's University of London.
authors.forename: Robin
authors.initials: R
authors.lastname: Shattock
authors.affiliation: Center for Prevention Research, UCLA AIDS Institute, David Geffen School of Medicine at UCLA, CA.
authors.forename: Peter
authors.initials: P
authors.lastname: Anton
authors.affiliation: AIDS Vaccine Program SAIC-Frederick, Inc., NCI-Frederick, MD.
authors.forename: Robert
authors.initials: R
authors.lastname: Gorelick
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: Welsh School of Pharmacy, Cardiff University, Cardiff, CF10 3NB, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: McGuigan
authors.affiliation: Welsh School of Pharmacy, Cardiff University, Cardiff, CF10 3NB, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: Derudas
authors.affiliation: McGill University, Department of Microbiology and Immunology, Montreal, Québec, Canada.
authors.forename: Matthias
authors.initials: M
authors.lastname: Götte
authors.affiliation: Emory University School of Medicine, Veterans Affairs Medical Center, Decatur, GA.
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
authors.forename: Leonid
authors.initials: L
authors.lastname: Margolis
mesh_terms: D000212:Acyclovir / Q000378:metabolism / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology*; D001711:Biotransformation; D002478:Cells, Cultured; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006561:Herpes Simplex / Q000150:complications / Q000821:virology*; D018258:Herpesvirus 2, Human / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008221:Lymphoid Tissue / Q000821:virology; D010766:Phosphorylation; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D000212:Acyclovir
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