Lisco Andrea, Vanpouille Christophe, Tchesnokov Egor P, Grivel Jean-Charles, 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
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
McGill University, Department of Microbiology and Immunology, Montreal, Québec, Canada.
Cell Host Microbe. 2008 Sep 11;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 RT inhibitors.
对于大多数病毒而言，需要有针对独特病毒分子特性的抗菌药物。阿昔洛韦（ACV）就是这样一种药物。它仅由人疱疹病毒（HHV）激酶激活成为人疱疹病毒DNA聚合酶抑制剂，因此不会抑制其他病毒。在此，我们表明，ACV在HHV共感染的人体组织中可抑制HIV-1，但在无HHV的组织或细胞培养物中则不然。然而，添加感染HHV-6的细胞会使这些培养物对抗HIV的阿昔洛韦活性敏感。我们推测，这种对HIV的抑制作用需要HHV激酶对ACV进行磷酸化。事实上，一种单磷酸化的阿昔洛韦前药绕过了HHV对HIV抑制的需求。此外，磷酸化的阿昔洛韦直接抑制HIV-1逆转录酶（RT），终止DNA链延伸，并能将RT捕获在终止位点。这些数据表明，ACV的抗HIV-1活性可能有助于HIV/HHV共感染患者对ACV治疗的反应，并可为开发新型HIV-1 RT抑制剂的策略提供指导。
