Myrcludexthe study of hepatitis B and D virus interactions and preclinical drug

tonychant

Abstract
No specific drugs are currently available against hepatitis delta virus (HDV), a defective virus leading to the most severe form of chronic viral hepatitis in man. The lack of convenient HDV infection models has hampered the development of effective therapeutics. In this study, naïve and hepatitis B virus (HBV) chronically infected humanized uPA/SCID mice were employed to establish a small animal model of HBV/HDV coinfection and superinfection. For preclinical antiviral drug evaluation, the GMP version of the myristoylated preS-peptide (Myrcludex-B), a lipopeptide derived from the pre-S1 domain of the HBV envelope, was applied to prevent de novo HBV/HDV coinfection in vivo. Virological parameters were determined at serological and intrahepatic level both by real-time polymerase chain reaction (PCR) and by immunohistochemistry. Establishment of HDV infection was highly efficient in both HBV-infected and naïve chimeric mice with HDV titers rising up to 1 × 10E9 copies/mL. Notably, HDV superinfection led to a median 0.6log reduction of HBV viremia, which although not statistically significant suggests that HDV may hinder HBV replication. In the setting of HBV/HDV simultaneous infection, a majority of human hepatocytes stained HDAg-positive long before HBV spreading was completed, confirming that HDV can replicate intrahepatically also in the absence of HBV infection. Furthermore, the increase of HBV viremia and intrahepatic cccDNA loads was significantly slower than in HBV mono-infected mice. Treatment with the HBV entry inhibitor Myrcludex-B, efficiently hindered the establishment of HDV infection in vivo. CONCLUSION: We established an efficient model of HBV/HDV infection to exploit mechanisms of viral interference in human hepatocytes and to test the efficacy of an HDV-entry inhibitor in vivo.

tonychant

人性化嵌合UPA为B型肝炎和D病毒的相互作用和临床前药物评价研究的小鼠模型。
抽象
目前没有具体的药物对丁型肝炎病毒（HDV），一个有缺陷病毒导致的最严重的形式，在人类慢性病毒性肝炎。方便HDV感染模型的缺乏阻碍了有效的治疗方法的发展。在这项研究中，天真和B型肝炎病毒（HBV）慢性感染人性化的UPA/ SCID小鼠建立乙肝/ HDV混合感染和二重感染的小动物模型。抗病毒药物的临床前药物评价，myristoylated的preS肽（Myrcludex-B）的HBV包膜前S1域派生脂，GMP版本适用于防止从头乙肝/ HDV混合感染在体内的。病毒学参数测定血清和肝内实时聚合酶链反应（PCR）和免疫组化水平。 HDV感染的建立高效的HDV滴度上升到1×10E9拷贝/ ml的HBV感染和天真的嵌合体小鼠。值得注意的是，HDV的重叠导致中位数0.6log减少乙肝病毒血症，这虽然没有统计学意义，表明的HDV可能阻碍HBV复制。多数人肝细胞中的乙肝/ ​​HDV同时感染的设置，染色D抗原的阳性长之前，完成了乙肝病毒的传播，确认的HDV可以复制​​intrahepatically在乙肝病毒感染的情况下也。此外，乙肝病毒血症和肝内cccDNA的负荷增加，显着高于HBV单一感染小鼠慢。乙肝病毒进入的抑制剂Myrcludex-B的治疗，有效地阻碍体内建立HDV感染。结论：我们建立了乙肝/ HDV感染的有效模式，利用在人类肝细胞的病毒干扰的机制，并在体内测试的HDV进入抑制剂的疗效。

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