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

摘要 丁型肝炎病毒（HDV）是B型肝炎病毒（HBV）的亚病毒因子。它使用HBV包膜蛋白（或 表面抗原，HBsAg）形成其病毒体并通过HBV受体感染肝细胞。约2.57亿人 全世界约有2000万人慢性感染HBV，其中约2000万人也慢性感染HDV。HDV 感染会导致额外的肝脏损伤，并可能加速肝脏疾病，导致更迅速和更频繁的 肝硬化，并增加肝细胞癌的风险。抗HBV药物不能阻断HDV感染， 临床上存在直接靶向HDV的药物。HDV感染的机制尚不完全清楚，这影响了 治疗方案。HDV-HBV和HDV-宿主相互作用是复杂的，研究不足。调控 通过对HBV感染的免疫应答的HDV生命周期实际上未被探索，这是本研究的主题。 study.因此，HBV-宿主相互作用导致主要免疫缺陷病毒中出现免疫逃逸突变（IEM）。 HBsAg的抗原环（MAL）。IEM可使HBsAg难以被天然抗HBsAg抗体识别 并且免疫测定检测不到，导致HBV疫苗失败，促进移植肝的再感染， HBV，并促进慢性HBV感染的维持。IEM可以深刻地影响HBsAg的分泌， HBV病毒粒子。然而，了解IEM如何影响HDV组装和感染性，以及对 HDV通过抗HBsAg抗体（即，HDV抗原性）是非常有限的，绝大多数IEM不是 在这方面进行分析。我们发现HBsAg通过促进两种不同的功能来调节HDV的感染性 可以在功能上分开。它通过调节肝细胞的增殖来决定感染肝细胞的数量。 附件/条目。它还决定了HDV基因组的数量，进入后到达细胞核，并开始 通过调节运输和脱壳（感染细胞中包膜的丢失）来控制复制。我们的工作 表明病毒的传染性、传播性和重复感染性可能是该病毒建立的关键因素 和维持慢性HDV感染。此外，HDV组装的速率可以极大地影响HDV 传播/超级感染。MAL中的氨基酸可以影响HBsAg的产量/分泌，从而可以影响HDV 组装件.《仲裁示范法》预计将对（一）扣押/进入以及（二）可能的贩运/剥离涂层加以规范，因此， 来调节丁型肝炎病毒的传染性。MAL还调节抗HBsAg抗体对病毒体的识别。因此，在本发明中， 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使用HBV基因型A-D的HBsAg（大多数IEM被报道），将发现HBsAg携带者如何携带HBsAg， IEM可以调节HDV病毒粒子的分泌量，影响B型肝炎病毒对HDV病毒粒子的识别 免疫球蛋白（HBIg）。目的2使用上述携带HBsAg的天然IEM将发现IEM如何能够 调节HDV病毒粒子的感染性。拟议的研究将大大促进我们对 宿主调节（i）HDV-宿主相互作用，（ii）HBV-HDV相互作用，（iii）组装 和HDV的传染性，和（iv）HDV的持久性通过促进IEM在HBsAg中的出现。

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.