Saint Louis University School of Medicine, Department of Molecular Microbiology and Immunology, St. Louis, MO, USA; Saint Louis University School of Medicine, Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, St. Louis, MO, USA.
Saint Louis University School of Medicine, Department of Molecular Microbiology and Immunology, St. Louis, MO, USA.
Virology. 2014 May;456-457:300-9. doi: 10.1016/j.virol.2014.03.018. Epub 2014 Apr 24.
We previously found that human pegivirus (HPgV; formerly GBV-C) NS3 protease activity inhibits Human Immunodeficiency Virus (HIV) replication in a CD4+ T cell line. Given the protease׳s similarity to the Hepatitis C virus (HCV) NS3 protease, we characterized HPgV protease activity and asked whether it affects the type I interferon response or is inhibited by HCV protease antagonists. We characterized the activity of proteases with mutations in the catalytic triad and demonstrated that the HCV protease inhibitors Telaprevir, Boceprevir, and Danoprevir do not affect HPgV protease activity. HPgV NS3 protease cleaved MAVS but not TRIF, and it inhibited interferon responses sufficiently to enhance growth of an interferon-sensitive virus. Therefore, HPgV׳s inhibition of the interferon response could help promote HPgV persistence, which is associated with clinical benefits in HIV-infected patients. Our results also imply that HCV protease inhibitors should not interfere with the beneficial effects of HPgV in HPgV/HCV/HIV infected patients.
我们之前发现人类戊型肝炎病毒（HPgV；以前称为 GBV-C）的 NS3 蛋白酶活性可抑制 CD4+T 细胞系中的人类免疫缺陷病毒（HIV）复制。鉴于该蛋白酶与丙型肝炎病毒（HCV）NS3 蛋白酶相似，我们对 HPgV 蛋白酶活性进行了表征，并探讨了其是否会影响 I 型干扰素反应或是否被 HCV 蛋白酶拮抗剂抑制。我们对催化三联体突变的蛋白酶活性进行了表征，并证实 HCV 蛋白酶抑制剂 Telaprevir、Boceprevir 和 Danoprevir 不会影响 HPgV 蛋白酶活性。HPgV NS3 蛋白酶可切割 MAVS，但不能切割 TRIF，并且其可充分抑制干扰素反应，从而促进干扰素敏感型病毒的生长。因此，HPgV 对干扰素反应的抑制作用可能有助于促进 HPgV 的持续存在，这与 HIV 感染患者的临床益处相关。我们的研究结果还表明，HCV 蛋白酶抑制剂不应干扰 HPgV 在 HPgV/HCV/HIV 感染患者中的有益作用。
