Acyclovir is activated into a HIV-1 reverse transcriptase inhibitor

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Cell Host Microbe. 2008 Sep 11;4(3):260-70.

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 A, Vanpouille C, Tchesnokov EP, Grivel JC, 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.Eunice Kennedy

Shriver National Institute of Child Health and Human Development, National

Institutes of Health, Bethesda, MD 20892, USA. PMID: 18779052