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Acyclovir is activated into a HIV-1 reverse transcriptase inhibitor in herpesvirus-infected human tissues
journal contribution
posted on 2023-06-08, 21:54 authored by Andrea Lisco, Christophe Vanpouille, Egor P Tchesnokov, Jean-Charles 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 MargolisFor 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.
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Publication status
- Published
File Version
- Published version
Journal
Cell Host and MicrobeISSN
1931-3128Publisher
ElsevierExternal DOI
Issue
3Volume
4Page range
260-270Department affiliated with
- Chemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2015-07-28First Open Access (FOA) Date
2015-07-28First Compliant Deposit (FCD) Date
2015-07-28Usage metrics
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