Regulation of HDV life cycle by the immune response to HBV infection

摘要 丁型肝炎病毒(HDV)是乙肝病毒(HBV)的一种亚病毒病原体。它使用乙肝病毒包膜蛋白(或 表面抗原)形成病毒粒子，通过乙肝病毒受体感染肝细胞。约2.57亿人 全世界都有慢性乙肝病毒感染者，其中约2000万人同时慢性感染丁型肝炎病毒。HDV 感染会造成额外的肝脏损害，并可能加速肝脏疾病，导致更快和更频繁的 肝硬变，增加患肝细胞癌的风险。抗乙肝药物不能阻断HDV感染，而且没有 临床上存在直接针对HDV的药物。HDV感染的机制还不完全清楚，这影响了 治疗方案。HDV-乙肝病毒和HDV-宿主之间的相互作用是复杂的，研究还不够深入。监管 HDV的生命周期对乙肝病毒感染的免疫反应几乎是未知的，这是这个主题 学习。因此，乙肝病毒与宿主的相互作用导致了免疫逃逸突变(IEM)在主要 乙肝表面抗原抗原环(MAL)。IEMS可使天然抗-HBs抗体难以识别HBs Ag 和免疫分析无法检测到的，导致乙肝疫苗失败，促进移植肝脏的再次感染 乙肝病毒，促进慢性乙肝病毒感染的维持。IEMS可以深刻地影响乙肝表面抗原和 乙肝病毒粒子。然而，对IEM如何影响HDV组装和传染性的理解，以及对 由抗-HBs Ag抗体(即HDV抗原性)产生的HDV是非常有限的，绝大多数IEM不是 在这方面进行了分析。我们发现，乙肝表面抗原通过促进两种不同的功能来调节HDV的感染性 它们可能在功能上是分开的。它通过调节受感染的肝细胞的数量 附件/条目。它还决定了进入后到达细胞核并开始的HDV基因组的数量 通过调节运输和脱壳(受感染细胞中的包膜丢失)进行复制。我们的工作 提示病毒的传染性、传播性和双重感染可能是病毒建立的关键因素。 和维持慢性HDV感染。此外，HDV的组装速度会对HDV产生很大影响 传播/超级感染。MAL中的氨基酸可以影响乙肝表面抗原的产量/分泌，从而影响HDV。 集合。预计《仲裁示范法》将规范(I)附着/入境和(Ii)可能的贩运/脱衣，因此 调节HDV的传染性。MAL还调节抗HBs Ag抗体对病毒粒子的识别。因此， 我们的中心假设是，IEM可以显著影响HDV的组装、感染性和抗原性。 目的1利用乙肝病毒A-D型(报道最多的IEM)的乙肝表面抗原，将发现乙肝表面抗原是如何携带的 IEMS可调节分泌的HDV病毒粒子的产量，并影响乙肝病毒对HDV病毒粒子的识别 免疫球蛋白(HBIg)。目的2使用上述携带乙肝表面抗原的天然免疫母细胞将发现免疫母细胞如何 调节HDV病毒粒子的传染性。拟议的研究将大大加深我们对 宿主调节(I)HDV-宿主相互作用、(Ii)乙肝病毒-HDV相互作用、(Iii)组装的机制 和HDV的感染性，以及(Iv)通过促进HBs Ag中的IEM的出现来维持HDV的持久性。

Abstract Hepatitis delta virus (HDV) is a sub-viral agent of hepatitis B virus (HBV). It uses HBV envelope proteins (or surface antigen, HBsAg) to form its virions and infect hepatocytes via HBV receptor. About 257 million people worldwide are chronically infected with HBV, of which ~20 million are also chronically infected with HDV. HDV infection causes additional liver damage, and may accelerate liver disease, cause more rapid and frequent cirrhosis, and increase risk of hepatocellular carcinoma. Anti-HBV drugs do not block HDV infection, and no drugs exist in clinic that directly target HDV. Mechanism of HDV infection is not fully understood, which affects the treatment options. HDV-HBV and HDV-host interactions are complex and under-studied. The regulation of HDV life cycle by the immune response to HBV infection is practically unexplored, and it is the subject for this study. Thus, HBV-host interactions lead to emergence of the immune escape mutations (IEMs) in the major antigenic loop (MAL) of HBsAg. IEMs can make HBsAg poorly recognized by natural anti-HBsAg antibodies and undetectable by the immunoassays, cause HBV vaccine failure, facilitate re-infection of grafted liver with HBV, and promote maintenance of chronic HBV infection. IEMs can profoundly affect secretion of HBsAg and HBV virions. However, the understanding how IEMs affect HDV assembly and infectivity, and recognition of HDV by anti-HBsAg antibodies (i.e., HDV antigenicity) is very limited, and the vast majority of IEMs were not analyzed in this respect. We found that HBsAg regulates HDV infectivity by facilitating two distinct functions that could be functionally separated. It determines the number of the infected hepatocytes by regulating the attachment/entry. It also determines the number of HDV genomes that post-entry reach the nucleus and start the replication by regulating the trafficking and uncoating (loss of the envelope in infected cell). Our work suggested that the virus infectivity, spread and super-infection are likely critical factors for the establishment and maintenance of chronic HDV infection. In addition, the rate of HDV assembly can greatly affect HDV spread/super-infection. The amino acids in MAL can affect HBsAg yield/secretion, and thus can affect HDV assembly. MAL is expected to regulate the (i) attachment/entry and (ii) possibly trafficking/uncoating, and thus to regulate HDV infectivity. MAL also regulates the recognition of the virions by anti-HBsAg antibodies. Thus, our central hypothesis is that IEMs could considerably affect the assembly, infectivity and antigenicity of HDV. Aim 1 using HBsAg of HBV genotypes A-D (for which most IEMs were reported) will find how HBsAg bearing IEMs can regulate the yield of secreted HDV virions and affect the recognition of HDV virions by hepatitis B immune globulin (HBIg). Aim 2 using the above mentioned HBsAg bearing natural IEMs will find how IEMs can regulate the infectivity of HDV virions. The proposed study will considerably advance our understanding of the mechanisms by which the host regulates (i) HDV-host interactions, (ii) HBV-HDV interactions, (iii) assembly and infectivity of HDV, and (iv) HDV persistence via facilitating the emergence of IEMs in HBsAg.