UNIverse - Public Research Portal
Project cover

Role of Hepatitis C Virus (HCV) RNA-Dependent RNA Polymerase NS5B activity in HCV pathogenesis, persistence, and regulation of antiviral defense in humans

Research Project
 | 
01.05.2014
 - 31.10.2015

Hepatitis C virus (HCV) is a positive-strand RNA virus infecting approximately 150 million persons worldwide. HCV infection can cause chronic liver disease and lead to liver cirrhosis and/or liver cancer. There is no vaccine for HCV, and current therapy has only limited efficiency and multiple side effects. HCV induces strong innate immune response within first days of infection, that includes production of type I IFN. This response leads to viral clearance in ~30% of patients, however, in other ~70% of cases infection becomes chronic. Mechanisms of HCV persistence and immune escape are poorly understood. For RNA viruses, it is believed that innate immune response is triggered solely by viral genome replication intermediates, such as double-stranded RNA (dsRNA) or 5'-triphosphate-containing (5'-ppp) RNA, generated by viral RNA-dependent RNA polymerases (RdRp). However, this is unlikely for HCV, as its replication takes place in hidden compartments, and viral RNA is, presumably, not exposed to innate immune sensors. It has been demonstrated recently that HCV RdRp (NS5B) can use host cell RNA as template and generate small dsRNA molecules that trigger IFN production in mouse livers and in cultured liver cells. We hypothesize, that this non-specific activity of HCV NS5B protein is the major activator of innate immunity in acute HCV infection in humans, and contributes to HCV persistence and immune regulation in chronic phase. The proposed study will aim at finding out how HCV NS5B activity and production of small dsRNA species affect the course and outcome of HCV infection. We will use human liver biopsies from infected patients, molecular biology and biochemistry techniques, next-generation sequencing and bioinformatics to characterize HCV-induced small dsRNA species and analyze their role in host-virus interactions in HCV infection. A thorough understanding of these interactions will facilitate the development of better therapies and a preventive vaccine.

Funding

Role of Hepatitis C Virus (HCV) RNA-Dependent RNA Polymerase NS5B activity in HCV pathogenesis, persistence, and regulation of antiviral defense in humans

Schweizerische Universitätskonferenz SUK (GrantsTool), 05.2014-10.2015 (18)
PI : Heim, Markus H..

Members (1)

MALE avatar

Markus H. Heim

Principal Investigator