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

• Applicant: Professorin Dr. Reinhild Prange
• Subject Area: Virology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2012 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 215126631

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.

• DFG Programme: Research Grants