Acyclovir is activated into a HIV-1 reverse transcriptase inhibitor in herpesvirus-infected human tissues

作者：Lisco Andrea; Vanpouille Christophe; Tchesnokov Egor P; Grivel Jean Charles; Biancotto Angelique; Brichacek Beda; Elliott Julie; Fromentin Emilie; Shattock Robin; Anton Peter; Gorelick Robert; Balzarini Jan; McGuigan Christopher; Derudas Marco; Goette Matthias; Schinazi Raymond F; Margolis Leonid^*

来源：Cell Host & Microbe, 2008, 4(3): 260-270.

DOI：10.1016/j.chom.2008.07.008

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 FIT inhibitors.

• 出版日期2008-9-11
• 单位河北医科大学