Acyclovir is activated into a HIV-1 reverse transcriptase inhibitor in herpesvirus-infected human tissues
Acyclovir is activated into a HIV-1 reverse transcriptase inhibitor in herpesvirus-infected human tissues
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DOI：
10.1016/j.chom.2008.07.008
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发表时间：
2008-09-11
影响因子：
30.3
通讯作者：
Margolis, Leonid
中科院分区：
文献类型：
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作者：
Lisco, Andrea;Vanpouille, Christophe;Margolis, Leonid
对于大多数病毒，需要针对独特病毒分子特性的抗菌剂。阿昔洛韦（ACV）就是这样一种药物。它仅被人类疱疹病毒（HHV）激酶激活为人类疱疹病毒（HHV）DNA聚合酶抑制剂，因此不抑制其他病毒。在这里，我们表明，ACV抑制HIV-1在HHV共感染的人体组织，但不是在无HHV的组织或细胞培养。然而，添加HHV-6感染的细胞使得这些培养物对抗HIV ACV活性敏感。我们假设这种HIV抑制需要HHV激酶对ACV的磷酸化。事实上，ACV单磷酸化前药绕过了HIV抑制的HHV要求。此外，磷酸化的ACV直接抑制HIV-1逆转录酶（RT），终止DNA链的延伸，并可以在终止位点捕获RT。这些数据表明，ACV抗HIV-1活性可能有助于HIV/HHV合并感染患者对ACV治疗的反应，并可指导新的HIV-1 FIT抑制剂的开发策略。
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.