Human monoclonal antibodies for the treatment and prevention of hepatitis C virus infection

Chronic Hepatitis C virus is a blood-borne infection that can result in development of very serious liver disease. The most severe forms of liver disease can only be treated by liver transplantation. Re-infection of the transplanted liver is often rapid and current treatments are ineffective in this group of patients. Alternative therapies are sought, particularly for this group of patients. Therefore, we will isolate human monoclonal antibodies from individuals who have naturally cleared virus. These antibodies will provide important lead therapies to prevent transplant re-infection and will also provide important information that will help vaccine design. An important aspect of this work will be to study how the virus changes during infection, so that those antibodies that target the widest range of virus strains are identified.

Hepatitis C virus (HCV) is the major causative agent of non-A, non-B hepatitis. HCV infection is found throughout the world and the prevalence of anti-HCV antibodies range from 0.2 to 2% in most developed countries. Acute HCV infection results in viral clearance in 20% of individuals and there is evidence that the patients who resolve infection harbour cross-reactive neutralising antibodies, whereas those who develop chronic infection do not. Evolution of viral quasispecies is also more rapid in individuals with chronic infection, yet its relationship to host antibody response is poorly understood. Here, we will isolate and characterise human monoclonal antibodies from individuals with acute infection and determine antibody correlates associated with clearance. We will also determine E1E2 glycoprotein gene evolution to define mechanisms of escape. This information will be important in defining the best epitopes to target in vaccine design. In addition, this project will also deliver monoclonal antibodies with significant therapeutic potential. End-stage liver disease is a frequent result of chronic HCV infection, and this requires liver transplantation. Long term prognosis is poor due to re-infection of the grafted liver and poor treatment outcomes in this group of patients. Therapeutic antibodies will have huge potential in this clinical setting. This proposal will provide essential foundation knowledge and lead compounds to help combat a disease of major public health importance, which is the principal cause of primary liver cancer.