The hepatitis C virus was discovered only seven years ago and the pathogenesis of hepatitis C is far from clear. This project aims at the identification and characterisation of important immunological mechanisms of viral elimination on the one hand and factors mediating viral persistence and chronicity on the other. On the basis of the expected results the development of a preventive vaccine and new immunotherapies are planned.
To study the complex interaction of the various antiviral immune mechanisms and the infecting hepatitis C viral population we take advantage of the participants' expertise in the fields of cellular and humoral immunology and molecular virology. It is the central aim of this project to study the various parameters in the same patients with acute hepatitis C. By comparison of patients with self-limited acute hepatitis C and those with evolving chronic hepatitis C, important immunological mechanisms of viral clearance should be identified. At the same time the study of the infecting viral population, determination of the quasispecies variety and evolving mutations in T cell or antibody epitopes may reveal the contribution of viral heterogeneity to viral persistence.
From the different patient groups virus-specific CD4+ and CD8+ T cell clones will be isolated and characterised. Using different approaches, several hypotheses about the regulation of the T cell response will be tested (cytokine pattern, induction of anergy, exhaustion, suppression, antagonism). The functional interaction of CD4+ and CD8+ T lymphocytes will be studied to characterise the contribution of each cell type to viral elimination. Fine mapping of T cell epitopes and sequencing of the respective viral region will allow the direct determination of the influence of viral mutations on the antiviral T cell response (viral escape vs. antagonism). Similar studies will be performed for the humoral immune response, focusing on antibodies to the hypervariable regions of the envelope proteins which are the best candidates for virus neutralising antibodies.
Results from those studies should lead to new concepts for a preventive vaccine and/or new immunotherapeutic approaches. These new strategies will first be tested in in-in-vitro models. Eventually clinical trials will be set up to test these new developments.
Funding SchemeCSC - Cost-sharing contracts
W12 0NN London
171 63 Solna