Morphogenesis of hepatitis B and hepatitis D virus particles: Strategies, mechanisms and host factors

乙型肝炎和丁型肝炎病毒颗粒的形态发生：策略、机制和宿主因素

• 批准号: 215126631
• 负责人: Professorin Dr. Reinhild Prange
• 金额: --
• 依托单位: Institut für Virologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/215126631?language=en
• 关键词: Morphogenesis; hepatitis; virus; particles; Strategies

The human hepatitis B virus (HBV) is an enveloped pararetrovirus that causes acute and chronic liver inflammation. Persistent HBV infections often result in fatal liver failure and globally rank among the most common infectious diseases. Concomitant infections with the hepatitis D virus (HDV), a satellite of HBV, usually enhance liver pathogenesis. Currently approved therapies are limited and in most cases non-curative. Due to their limited coding capacities, both viruses are heavily dependent on the host cell and have developed diverse strategies to exploit cellular functions. Our investigations on HBV particle morphogenesis and its coordination by host factors reveal that viral particles (VPs) bud at intracellular membranes by the exploitation of cellular autophagy complexes, Rab GTPases, ubiquitin adaptors, ubiquitin ligases and specific proteins of the multivesicular endosome network (ESCRT). Besides VPs, infected hepatocytes also secrete in huge amounts non-infectious, subviral envelope particles (SVPs), also known as HBsAg. SVPs are thought to exhaust immune responses thereby contributing to viral persistence and pathogenesis. In this renewal proposal, we will extend our research to HDV and focus on the HBV envelope that is shared by both pathogens and forms the scaffold of SVPs. As an integral aim, we will explore mechanisms and host factors guiding SVP/viral envelope biogenesis. In particular, based on our preparatory works, we will decipher the role of the cellular coat protein complex II (COPII) vesicle budding machinery in HBV and HDV biology. The COPII complex, in conjunction with the Rab1 GTPase and TANGO1 family proteins, is instrumental in guiding cargo trafficking within the secretory system. Proteomics-based studies revealed an interplay between the HBV envelope and a cargo adaptor subunit of COPII. By using cell culture systems combined with cell biological methods, we will investigate if and how HBV and HDV may engage the COPII budding and trafficking machinery for benefit. By probing molecular insights into the virus envelope-COPII interaction, we are expecting evidence which will help to design therapeutic approaches targeting the virus-host crosstalk. Cell penetrating interfering peptides will be developed and approved for their potential to inhibit virus particle release, ideally affecting SVP and VP egress of both, HBV and HDV. Moreover, the newly setup of an HDV replication system in our lab enables to study auxiliary host factor requirements of this poorly characterized pathogen.

人肝炎B病毒（HBV）是一种有包膜的副逆转录病毒，可引起急性和慢性肝脏炎症。持续的HBV感染通常导致致命的肝功能衰竭，在全球范围内是最常见的传染病之一。伴随感染丁型肝炎病毒（HDV），HBV的卫星，通常会增强肝脏的发病机制。目前批准的治疗方法是有限的，在大多数情况下是不治愈的。由于其有限的编码能力，这两种病毒都严重依赖于宿主细胞，并已开发出不同的策略来利用细胞功能。我们对HBV颗粒形态发生及其与宿主因素的协调的研究表明，病毒颗粒（VP）通过利用细胞自噬复合物，Rab GTP酶，泛素衔接子、泛素连接酶和多泡内体网络（ESCRT）的特异性蛋白质。除VP外，感染的肝细胞还分泌大量非感染性亚病毒包膜颗粒（SVP），也称为HBsAg。SVP被认为耗尽免疫应答，从而导致病毒持续存在和发病。在这项更新提案中，我们将把我们的研究扩展到HDV，并专注于HBV包膜，该包膜由两种病原体共享并形成SVP的支架。作为一个整体的目标，我们将探索机制和宿主因素指导SVP/病毒包膜生物合成。特别是，基于我们的准备工作，我们将破译的作用，细胞外壳蛋白复合物II（COPII）囊泡出芽机制在HBV和HDV生物学。COPII复合物与Rab 1 GTdR和TANGO 1家族蛋白结合，有助于引导分泌系统内的货物运输。基于蛋白质组学的研究揭示了HBV包膜和COPII的货物接头亚基之间的相互作用。通过使用细胞培养系统结合细胞生物学方法，我们将研究HBV和HDV是否以及如何参与COPII出芽和贩运机制。通过对病毒干扰素-COPII相互作用的分子机制的深入研究，我们期待着能够提供证据，帮助设计针对病毒-宿主干扰的治疗方法。将开发并批准细胞穿透干扰肽，因为它们具有抑制病毒颗粒释放的潜力，理想地影响HBV和HDV的SVP和VP排出。此外，我们实验室新建立的HDV复制系统能够研究这种特征不明显的病原体的辅助宿主因子需求。