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.
Lisco
Andrea
A
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
Vanpouille
Christophe
C
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
Tchesnokov
Egor P
EP
McGill University, Department of Microbiology and Immunology, Montreal, Québec, Canada.
Grivel
Jean-Charles
JC
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
Biancotto
Angélique
A
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
Brichacek
Beda
B
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
Elliott
Julie
J
Center for Prevention Research, UCLA AIDS Institute, David Geffen School of Medicine at UCLA, CA.
Fromentin
Emilie
E
Emory University School of Medicine, Veterans Affairs Medical Center, Decatur, GA.
Shattock
Robin
R
St. George's University of London.
Anton
Peter
P
Center for Prevention Research, UCLA AIDS Institute, David Geffen School of Medicine at UCLA, CA.
Gorelick
Robert
R
AIDS Vaccine Program SAIC-Frederick, Inc., NCI-Frederick, MD.
Balzarini
Jan
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
McGuigan
Christopher
C
Welsh School of Pharmacy, Cardiff University, Cardiff, CF10 3NB, UK.
Derudas
Marco
M
Welsh School of Pharmacy, Cardiff University, Cardiff, CF10 3NB, UK.
Götte
Matthias
M
McGill University, Department of Microbiology and Immunology, Montreal, Québec, Canada.
Schinazi
Raymond F
RF
Emory University School of Medicine, Veterans Affairs Medical Center, Decatur, GA.
Margolis
Leonid
L
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
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
D019380:Anti-HIV Agents; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D000212:Acyclovir
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