Eliminating hepatitis B by antagonizing cellular inhibitors of apoptosis
Eliminating hepatitis B by antagonizing cellular inhibitors of apoptosis
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DOI：
10.1073/pnas.1502400112
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发表时间：
2015-05-05
影响因子：
11.1
通讯作者：
Pellegrini, Marc
中科院分区：
文献类型：
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作者：
Ebert, Gregor;Allison, Cody;Pellegrini, Marc
我们已经证明，细胞凋亡抑制蛋白(CIAP)通过阻止肿瘤坏死因子(TNF)介导的对受感染细胞的杀伤/死亡来损害对乙肝病毒(HBV)感染的清除。一个具有深远治疗意义的关键问题是，这一发现能否转化为促进消除受感染细胞的药物的开发。CIAPs的药物抑制剂被开发为癌症治疗药物，以促进肿瘤坏死因子介导的肿瘤杀伤。这些药物也被称为Smac模拟物，因为它们模拟内源性蛋白Smac/Diablo的作用，而Smac/Diablo拮抗CIAP功能。在这里，我们使用免疫活性的慢性乙肝病毒感染的小鼠模型显示，Birinapant和其他Smac模拟物能够迅速降低血清HBVDNA和血清乙肝表面抗原，并促进含有乙肝核心抗原的肝细胞的清除。Smac模拟物治疗乙肝病毒感染的疗效取决于它们的化学成分、宿主CD4(+)T细胞和肿瘤坏死因子。Birinapant增强了恩替卡韦的能力，恩替卡韦是一种抗病毒核苷类似物，可以减少乙肝病毒感染动物体内病毒DNA的产生。这些结果表明，Birinapant和其他Smac类似物可能在治疗乙肝病毒感染和其他细胞内感染方面有疗效。
We have shown that cellular inhibitor of apoptosis proteins (cIAPs) impair clearance of hepatitis B virus (HBV) infection by preventing TNF-mediated killing/death of infected cells. A key question, with profound therapeutic implications, is whether this finding can be translated to the development of drugs that promote elimination of infected cells. Drug inhibitors of cIAPs were developed as cancer therapeutics to promote TNF-mediated tumor killing. These drugs are also known as Smac mimetics, because they mimic the action of the endogenous protein Smac/Diablo that antagonizes cIAP function. Here, we show using an immunocompetent mouse model of chronic HBV infection that birinapant and other Smac mimetics are able to rapidly reduce serum HBV DNA and serum HBV surface antigen, and they promote the elimination of hepatocytes containing HBV core antigen. The efficacy of Smac mimetics in treating HBV infection is dependent on their chemistry, host CD4(+) T cells, and TNF. Birinapant enhances the ability of entecavir, an antiviral nucleoside analog, to reduce viral DNA production in HBV-infected animals. These results indicate that birinapant and other Smac mimetics may have efficacy in treating HBV infection and perhaps, other intracellular infections.