Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein
Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein
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DOI：
10.1038/nbt1389
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发表时间：
2008-03-01
影响因子：
46.9
通讯作者：
Urban, Stephan
中科院分区：
文献类型：
--
作者：
Petersen, Joerg;Dandri, Maura;Urban, Stephan
3.6亿人慢性感染人类B肝炎病毒（HBV），因此容易发生肝硬化和肝细胞癌（1）。由于批准的治疗方案-调节患者的抗病毒防御或抑制病毒逆转录酶-通常是非治愈性的，因此需要干扰其他HBV复制步骤的策略。在我们证明来自大HBV包膜蛋白的酰化肽在体外阻断病毒进入（2-5）的基础上，我们使用免疫缺陷型尿激酶型纤溶酶原激活物（uPA）小鼠（用原代人或Tupaia belangeri肝细胞重新填充），证明了它们在体内预防HBV或绒猴肝炎B病毒感染的适用性（6，7）。肽在肝脏中的积累、其非凡的抑制效力和特定的作用方式允许以非常低的剂量皮下递送。因此，抑制嗜肝DNA病毒进入构成了预防原发性HBV感染的治疗方法，例如肝移植后，并且还可能抑制慢性感染患者中的病毒传播。
360 million people are chronically infected with the human hepatitis B virus ( HBV) and are consequently prone to develop liver cirrhosis and hepatocellular carcinoma(1). As approved therapeutic regimens-which modulate patients' antiviral defenses or inhibit the viral reverse transcriptase-are generally noncurative, strategies interfering with other HBV replication steps are required. Expanding on our demonstration that acylated peptides derived from the large HBV envelope protein block virus entry in vitro(2-5), we show their applicability to prevent HBV or woolly monkey hepatitis B virus infection in vivo, using immunodeficient urokinase-type plasminogen activator ( uPA) mice repopulated with primary human or Tupaia belangeri hepatocytes(6,7). Accumulation of the peptides in the liver, their extraordinary inhibitory potency and specific mode of action permit subcutaneous delivery at very low doses. Inhibition of hepadnavirus entry thus constitutes a therapeutic approach to prevent primary HBV infection, such as after liver transplantation, and might also restrain virus spread in chronically infected patients.