Characterization of differences in viral clearance mechanisms on hepatitis delta virus species tropism

• Applicant: Elham Shirvani Dastgerdi, Ph.D.
• Subject Area: Virology ; Gastroenterology ; Immunology
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 318898354

Delta hepatitis, caused by co- or super-infection of hepatitis D virus (HDV) in hepatitis B virus (HBV)-infected patients, is the most severe form of chronic hepatitis since infection commonly leads to progression of hepatic fibrosis, cirrhosis and increased risk of hepatocellular carcinoma. Globally, about 360 million people are chronically infected with HBV, of which about 15-20 million are positive for HDV antibodies. Although both humoral and cellular immune responses are induced against HDV, they are not successful in disease recovery in the majority (80%-90%) of chronically infected patients which might be due to unknown mechanisms used by HDV to maintain its replication in infected cells. There is also no treatment that directly acts on HDV. The narrow host range of HDV which is limited to higher primates, especially humans and chimpanzees, and also the lack of adequate cell culture systems for delta virus infection have impeded progress toward curative therapies against HDV and therefore resulted in a great demand for developing alternative models that mimic HDV infection in human hepatocytes. HDV infection of the chimeric liver humanized mice models have shown that HDV can persist for fairly long periods of time in these cells, with HDV viremia only occurring upon super-infection with HBV suggesting a latent status of HDV infection which is rescued by HBV. In rodents, HDV life cycle is blocked at multiple steps including viral uptake and maintenance in the cells. Recently human sodium taurocholate co-transporting polypeptide (hNTCP) was identified as a receptor for HBV and HDV. Although hNTCP expression of murine cells facilitates HDV uptake but the virus is rapidly eliminated from murine hepatocytes. This has led us to hypothesize the absence of human host factors which support HDV replication or the presence of murine negative effectors that restrict completion of HDV life cycle in mouse cells. By defining the positive and negative regulators of HDV replication we not only aim to unravel the molecular determinants of HDV host tropism but also to develop an animal model with inheritable susceptibility to HDV infection. Moreover, identification of the essential host factors for HDV maintenance in human hepatocytes will highlight putative new targets for antiviral drug development. The identification of murine negative regulators, on the other hand, may suggest some cell intrinsic pathways to be triggered for antiviral-therapeutic- purposes.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Alexander Ploss, Ph.D.