Bortezomib Inhibits Hepatitis B Virus Replication in Transgenic Mice
Bortezomib Inhibits Hepatitis B Virus Replication in Transgenic Mice
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DOI：
10.1128/aac.01101-09
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发表时间：
2010-02-01
影响因子：
4.9
通讯作者：
Robek, Michael D.
中科院分区：
文献类型：
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作者：
Bandi, Prasanthi;Garcia, Mayra L.;Robek, Michael D.
细胞蛋白的药理学调节作为阻止病毒复制的一种手段已被提议作为一种替代抗病毒策略，该策略可能比其他策略更不易产生病毒耐药性。最近的证据表明，在病毒复制的细胞培养模型中，泛素-蛋白酶体途径与乙型肝炎病毒 (HBV) 生命周期的不同方面相互作用。因此，我们使用 HBV 转基因小鼠研究了蛋白酶体抑制对 HBV 体内复制的影响。蛋白酶体抑制剂硼替佐米（Velcade）可抑制体内蛋白酶体活性，用于临床治疗多发性骨髓瘤。我们发现，每公斤体重 1 毫克硼替佐米的单次静脉注射剂量可减少病毒复制长达 6 天。硼替佐米对 HBV 的抑制是剂量依赖性的，并且发生在病毒 RNA 和蛋白质表达之后的复制步骤中。 HBV 复制的减少不是由非特异性肝细胞毒性引起的，也不是通过诱导肝内干扰素反应间接介导的。因此，泛素-蛋白酶体途径的药理学操作可能代表治疗慢性乙型肝炎病毒感染的另一种治疗方法。
Pharmacological modulation of cellular proteins as a means to block virus replication has been proposed as an alternative antiviral strategy that may be less susceptible than others to the development of viral drug resistance. Recent evidence indicates that the ubiquitin-proteasome pathway interacts with different aspects of the hepatitis B virus (HBV) life cycle in cell culture models of virus replication. We therefore examined the effect of proteasome inhibition on HBV replication in vivo using HBV transgenic mice. The proteasome inhibitor bortezomib (Velcade) inhibits proteasome activity in vivo and is used therapeutically for the clinical treatment of multiple myeloma. We found that a single intravenous dose of 1 mg of bortezomib/kg of body weight reduced virus replication for as long as 6 days. The inhibition of HBV by bortezomib was dose dependent and occurred at a step in replication subsequent to viral RNA and protein expression. The reduction in HBV replication did not result from nonspecific hepatocellular toxicity and was not mediated indirectly through the induction of an intrahepatic interferon response. Thus, pharmacological manipulation of the ubiquitin-proteasome pathway may represent an alternative therapeutic approach for the treatment of chronic HBV infection.