The role of Hepatitis C virus glycoprotein-receptor polymorphism in viral pathogenesis

Hepatitis C virus (HCV) is a globally important virus that infects 170 million individuals world wide, resulting in progressive chronic liver disease. At present, there are limited therapies available for treating hepatitis C and there is an urgent need for the development of new agents that will cure infection. Viruses initiate infection by attaching to molecules or receptors on the cell surface, providing a target for therapeutic intervention. Recent advances have identified the cellular molecules defining HCV entry into liver cells. Studies from our laboratory have shown that HCV strains differ in their interaction with host cell receptors and this will have significant consequences for virus infectivity and spread in the liver. We hypothesise that such differences in HCV-receptor interactions will influence the ?relative fitness? of a virus to transmit and infect new individuals. We will use molecular and biological methods to study transmitting HCV strains to increase our understanding of the molecular events that define and limit virus transmission.

Hepatitis C Virus (HCV) poses a global health problem, with over 170 million infected individuals worldwide at risk of developing cirrhosis and hepatocellular carcinoma. A number of anti-viral replicase molecules are in clinical development, however, drug resistance and viral genotype-specific differences will limit their efficacy, demonstrating the need for combination therapies targeting different steps of the viral replication cycle.
Recent progress in the discovery of a strain of HCV that replicates in cell culture has enabled studies on virus assembly, release and entry, offering new targets for intervention. Studies from our laboratory have contributed to the growing understanding that HCV can disseminate via direct contacts between infected and na?ve cells. Cell-to-cell transfer of HCV is resistant to the neutralising effects of antibodies targeting the viral glycoproteins, providing a strategy for the virus to escape host immune responses. Whilst the majority of studies have focused on identifying host and viral pathways required for the genesis and release of infectious cell-free particles and inhibition of their entry into na?ve cells, cell-to-cell infection is poorly understood. We hypothesise that cell-to-cell infection is the dominant route for HCV to disseminate within the infected liver. The central aim of the current proposal is to define the mechanism(s) of cell-to-cell HCV infection and its role in virus dissemination within an infected host and transmission to new hosts in two clinical settings: recurrent HCV infection of the transplanted liver and mother to child vertical infection. Identification of the selective factors that define HCV spread and transmission will have major implications for the future treatment of HCV infection.
At present it is not clear how HCV quasispecies are maintained during chronic infection. A dominant mode of cell-to-cell HCV spread will limit virus trafficking between sites and the resulting viruses will follow independent evolutionary histories, i.e. become compartmentalised. Classic genetic models predict that evolution will occur more rapidly in a series of small isolated populations than in a single homogeneous pool. We propose to study the quasispecies structure of the HCV infected liver. This information will have a major impact on our understanding of HCV pathogenesis and the mechanism(s) underlying virus escape from host immune responses and anti-viral therapies.