Acyclovir Is Activated into a HIV-1 Reverse Transcriptase Inhibitor in Herpesvirus-Infected Human Tissues

Andrea Lisco, Christophe Vanpouille, Egor P. Tchesnokov, Jean-Charles B. Grivel, Angélique Biancotto, Beda Brichacek, Julie Elliott, Emilie Fromentin, Robin Shattock, Peter Anton, Robert Gorelick, Jan Balzarini, Christopher McGuigan, Marco Derudas, Matthias Götte, Raymond F. Schinazi, Leonid Margolis

Research output: Contribution to journalArticle

90 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)260-270
Number of pages11
JournalCell Host and Microbe
Volume4
Issue number3
DOIs
Publication statusPublished - 11 Sep 2008
Externally publishedYes

Fingerprint

Reverse Transcriptase Inhibitors
Acyclovir
Herpesviridae
HIV
HIV-1
Phosphotransferases
Cell Culture Techniques
Viruses
Nucleic Acid Synthesis Inhibitors
Human Herpesvirus 6
Human immunodeficiency virus 1 reverse transcriptase
RNA-Directed DNA Polymerase
Prodrugs
Phosphorylation
DNA

Keywords

  • CHEMBIO
  • MICROBIO

ASJC Scopus subject areas

  • Molecular Biology
  • Immunology and Microbiology(all)
  • Cancer Research

Cite this

Acyclovir Is Activated into a HIV-1 Reverse Transcriptase Inhibitor in Herpesvirus-Infected Human Tissues. / Lisco, Andrea; Vanpouille, Christophe; Tchesnokov, Egor P.; Grivel, Jean-Charles B.; Biancotto, Angélique; Brichacek, Beda; Elliott, Julie; Fromentin, Emilie; Shattock, Robin; Anton, Peter; Gorelick, Robert; Balzarini, Jan; McGuigan, Christopher; Derudas, Marco; Götte, Matthias; Schinazi, Raymond F.; Margolis, Leonid.

In: Cell Host and Microbe, Vol. 4, No. 3, 11.09.2008, p. 260-270.

Research output: Contribution to journalArticle

Lisco, A, Vanpouille, C, Tchesnokov, EP, Grivel, J-CB, Biancotto, A, Brichacek, B, Elliott, J, Fromentin, E, Shattock, R, Anton, P, Gorelick, R, Balzarini, J, McGuigan, C, Derudas, M, Götte, M, Schinazi, RF & Margolis, L 2008, 'Acyclovir Is Activated into a HIV-1 Reverse Transcriptase Inhibitor in Herpesvirus-Infected Human Tissues', Cell Host and Microbe, vol. 4, no. 3, pp. 260-270. https://doi.org/10.1016/j.chom.2008.07.008
Lisco, Andrea ; Vanpouille, Christophe ; Tchesnokov, Egor P. ; Grivel, Jean-Charles B. ; Biancotto, Angélique ; Brichacek, Beda ; Elliott, Julie ; Fromentin, Emilie ; Shattock, Robin ; Anton, Peter ; Gorelick, Robert ; Balzarini, Jan ; McGuigan, Christopher ; Derudas, Marco ; Götte, Matthias ; Schinazi, Raymond F. ; Margolis, Leonid. / Acyclovir Is Activated into a HIV-1 Reverse Transcriptase Inhibitor in Herpesvirus-Infected Human Tissues. In: Cell Host and Microbe. 2008 ; Vol. 4, No. 3. pp. 260-270.
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