Restoration of pathways implicated in T cell exhaustion following HCV infection.

Of the estimated 200 million individuals worldwide infected with hepatitis C virus (HCV), approximately 170 million people are chronic carriers, including 250,000 of the UK population. HCV infection can lead to chronic liver damage, cirrhosis and liver cancer: there is currently no broadly effective treatment and no vaccine. It is accepted that an effective immune response by the infected individual is required if the virus is to be cleared naturally. A major component of this response is generated through T cells. A greater understanding of this immune response, and the reasons for its failure, is central to developing effective antivirals for HCV. Development of in vitro replication systems to investigate aspects of viral lifecycle and interference thereof, has aided the field greatly, however, the availability of a suitable small animal model has hindered the discovery and development of antivirals for HCV. Since HCV only reliably infected man and chimpanzees, a surrogate model, the GB virus, B (GBV-B) infection of tamarins, is often used. GBV-B is highly similar to HCV: it is hepatotropic and its genome organisation and disease pathogenesis closely parallel that of HCV.

Specific pathways associated with a failed T cell immune response have been recognised in HCV infection in man. This failure is brought about by up-regulation of specific proteins on the surface of T cells, leading to an ?exhausted? phenotype. Recent studies have indicated that blocking the up-regulated proteins with specific antibodies may partially restore the normal function of the T cells. This highlights the potential for therapeutic intervention.

This programme of work is to confirm the identity of the T cell exhaustion pathways in GBV-B infection in the tamarin model. Using T cells isolated from the tamarins we will endeavour to reconstitute the function of the ?exhausted? T cells using cocktails of specific antibodies in vitro. Success with this study will enable us to consider a further application for funding to demonstrate the restoration of the normal T cell function in the animal model. This will establish the GBV-B/tamarin model as a suitable preclinical platform from which we can evaluate the effectiveness of these immune modulatory antibodies as antivirals for HCV.

An estimated 200 million people worldwide are infected with hepatitis C virus ? approximately four times as many as are infected with HIV. Up to 85% of those are chronically infected and develop health complications. HCV infection can cause extensive liver damage including cirrhosis resulting in liver failure, or hepatocellular carcinoma. Infection with HCV is the foremost reason for liver transplantation in Europe and the USA. There is no available protective vaccine for HCV and more than 50% of infected individuals fail to respond to current therapeutic regimens. Consequently there is an urgent need for a broadly effective antiviral approach to alleviate the enormous burden of HCV on global healthcare. There remains, however, a dearth of pre-clinical development of antivirals for HCV, in part due to the limited tropism of the virus. This emphasises the value of an available animal model to provide a platform from which candidate anti-viral agents can be evaluated.

T cell exhaustion has been reported as central to a persistent HCV infection. The phenomenon appears to involve a number of proteins found on the surface of T cells isolated from both blood and liver, and does not appear to be specific to an HCV genotype. This programme exploits the surrogate animal model for HCV, the GBV-B infection of tamarins. GBV-B virus is classed in the same family as HCV. Its genome organisation, site of replication and disease pathogenesis closely parallel that of HCV. We aim to identify the pathways associated with T cell exhaustion in the GBV-B-infected tamarin and restore the function in vitro, using antibody cocktails against specific T cell surface proteins down-regulated by the virus. Knowledge gained from this study will contribute towards the preclinical development of novel antiviral therapies for HCV