Many liver pathogens, like hepatitis C virus (HCV), have established mechanisms to subvert the host immune response and to establish persistent infection. Dissecting these mechanisms and gaining insight into factors that contribute to viral clearance versus chronicity in the liver is notoriously difficult. Access to human liver tissue is limited. The only immunocompetent animal model of HCV infection, the chimpanzee, is no longer readily available for research. However, we have recently succeeded in establishing the first immune- competent mouse model of an HCV-related virus, Norway rat hepacivirus (NrHV). Our preliminary characterization of this model revealed significant virological and immunological similarities with HCV infection in humans. This advance now opens the opportunity to interrogate hepatic antiviral immunity, host-virus interactions, viral adaptation, immune evasion strategies and pathogenesis of a hepatotropic virus at an unprecedented level. In this proposal we plan to comprehensively analyze innate and adaptive intrahepatic immune responses during hepacivirus infection in vivo and to define determinants of viral clearance. The natural host of NrHV is the rat. In immune-competent mice NrHV is cleared after several weeks of infection. Thus we plan to adapt this virus to the mouse, select for viral variants that can establish chronicity and systematically analyze mechanisms of host-adaptation and immune evasion. Through NrHV infection of the genetically diverse Collaborative Cross mouse colony at UNC, we will map the host genetic determinants of clearance and persistence. We anticipate that combined approaches of viral adaptation to the murine host and a host genetic screen will meet an important unmet need in establishing a robust model of virus-associated liver disease. Taken together, our proposed research will use a diverse and multidisciplinary approach to shed new light on hepatotropic virus infection in vivo. These insights should provide new strategies for vaccine development or treatment of virus-associated liver disease.

Public Health Relevance

Mechanisms that contribute to the persistence of hepatotropic viruses, such as hepatitis C virus (HCV), are not well understood. We have recently established the first immunocompetent mouse model of an HCV-related virus. With this new model we propose to systematically study immunity and host-virus interactions during a hepatotropic RNA virus infection with differential clearance and persistence outcomes in vivo. Combining virology, immunology and systems biology approaches we expect to provide new insights into determinants of viral clearance versus persistence in the liver that may help our ability to develop vaccine strategies and to treat viral infections and associated disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI131688-03
Application #
9645038
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Koshy, Rajen
Project Start
2017-03-15
Project End
2022-02-28
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Rockefeller University
Department
Microbiology/Immun/Virology
Type
Graduate Schools
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Trivedi, Sheetal; Murthy, Satyapramod; Sharma, Himanshu et al. (2018) Viral persistence, liver disease, and host response in a hepatitis C-like virus rat model. Hepatology 68:435-448
Billerbeck, Eva; Wolfisberg, Raphael; Fahn√łe, Ulrik et al. (2017) Mouse models of acute and chronic hepacivirus infection. Science 357:204-208