The role of neutralising antibodies in hepatitis C virus infection

Hepatitis C virus (HCV) is the major etiological agent of liver disease in most regions of the world. The majority of new infections become chronic and these individuals are at high risk for developing progressive liver disease. However, a minority of individuals (20%) resolve their infection and clear HCV to undetectable levels. We are interested in studying the immune parameters that distinguish these individuals from those where the virus persists. We will study the role of antibodies that have the potential to bind virus and prevent infection of new cells within the liver. Research findings from this proposal with immediate clinical relevance will be translated to the general public by interviews with the local press and through the MRC web site.

Hepatitis C virus (HCV) is the major etiological agent of liver disease in most regions of the world, with approximately 170 million individuals infected. Chronic HCV infection is also associated with disturbances in B lymphocyte function, including mixed cryoglobulinemia and B-cell lymphoma. Cellular and humoral immune responses are generated during HCV infection, however they are insufficient to effect viral clearance in the majority of individuals, with approximately 80% of new infections becoming chronic. However, the 20% of patients who resolve their infection provide an invaluable resource for studying the immune correlates of virus clearance. Recent studies of acute resolving infection provide compelling evidence that protective immunity exists: however, the immune factors that determine resolution versus chronic infection are poorly defined. The presence of an early and strong intrahepatic CD4+/CD8+ T-cell response appears to associate with early control of acute HCV infection. However, the role of nAbs in HCV infection and disease progression is unclear, largely due to the lack of assays that measure and quantify their activity. The recent discovery that retroviral pseudotypes bearing HCV envelope glycoproteins are infectious for cultured liver cell lines makes it possible to study the role of nAbs in HCV infection. Our current research shows that the majority of individuals who resolve acute HCV infection demonstrate a cross-reactive nAb response within the first year of infection, whereas, chronically infected patients develop nAb responses much later. We hypothesize that development of an early cross-reactive nAb response contributes to the immune control and clearance of HCV. To test this, we will study the evolution and specificity of the HCV specific nAb response in acute infection, comparing individuals who resolve HCV to those who progress to chronic infection. We will also study autologous nAb responses and determine if HCV evolves escape variants, with the goal of identifying the key differences in the early nAb response in patients who resolve acute HCV compared to those with persistent infection. These data will be critical both for the interpretation of current HCV env gp vaccine trials and for the future design of prophylactic and therapeutic vaccine immunogens. Finally, we will develop model systems to study HCV-B cell interaction(s) to address the mechanism(s) underlying the delayed appearance of nAbs in persistently infected patients and to elucidate the general B-cell abnormalities observed in chronically infected patients.