Interconnection of cellular autophagy and endosomal membrane trafficking and its role in hepatitis B virus replication, assembly, and release

• Applicant: Professor Dr. Mengji Lu
• Subject Area: Virology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 518382297

Hepatitis B virus (HBV) causes acute and chronic infection in humans. With estimated 290 million of HBV carriers worldwide, HBV infection remains a global threat to public health. Patients with chronic HBV infection are prone to cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Research efforts are directed to understand viral pathogenesis and underlying molecular mechanisms. Recently, HBV replication, assembly, and virion production in host cells have been extensively studied. Cellular endosomal trafficking and autophagy are two important processes for HBV assembly and virion production. Our previous studies showed a close association of HBV replication and HBsAg biogenesis with the autophagic process under some conditions, e.g. ER stress. In this proposed project, we will address the questions how autophagy and endosomal membrane trafficking cooperatively facilitate HBV replication, assembly, and release. Based on the available information, we propose a working model that HBV proteins and capsids may be captured and segregated by autophagosome compartments where HBV replication and assembly could take place. The autophagic process is not a bypass but could be a major pathway in connection with endosomes/multi vesicular bodies (MVBs) for HBV virion production. Though a major part of virions and subviral particles are degraded in autophago-lysosomes, a significant fraction evades the degradation and is exported through a not yet well-defined way. It has been demonstrated that autophagosomes could fuse with endosomes to form amphisomes. We hypothesize that HBV virions assembled in association with autophagosomes are sorted in amphisomes for export and released through MVBs. In this project, we will examine how antophagy and endosomal membrane trafficking are connected and coordinated to facilitate HBV assembly and release. At the same time, dynamic cellular membrane trafficking and fusion may allow HBV assembly and release. The processes like exosome biogenesis will also be examined for their potential role in HBV virion production. Our proposed project will clarify the contribution of different cellular mechanisms to HBV replication, assembly, and release from host cells and uncover potential viral targets for future drug development.

• DFG Programme: Research Grants