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Immunological basis of rational vaccine design for hepatitis C virus


The major objective of this proposal i8 to develop strategies to design a vaccine against the hepatitis C virus (HCV) through the analysis of the HCV specific immune response. In addition, the involvement of members of the combined group in vaccine development means that the necessary expertise is available to proceed rapidly from characterisation of immune responses to development of vaccine strategies. Hepatitis C virus (HCV) is an RNA virus with a high degree of sequence variability among different genotypes. It is responsible for the majority of blood borne chronic hepatitis. The prevalence of HCV infection around the world is between 0.4 and 2%. Chronic hepatitis develops in at least half the infected patients and progresses to liver cirrhosis in 20% of the chronic cases. Furthermore, most cases of hepato cellular carcinoma are caused by HCV.A first step in designing an HCV vaccine is the identification of the components involved in protective immunity. At present, little is known on the role the immune response plays in the course of HCV infection and whether antigenic variation among different HCV genotypes plays any role in the pathogenesis of hepatitis C.

We propose to characterize the immune response to the different HCV proteins inpatients with acute infection who succeed in clearing the virus and those who develop a chronic infection. In the course of these studies we will assess the importance of the immune response with respect to viral clearance and to the pathogenesis of liver disease.

To achieve these objectives we will define:
1) the antigenic specificity and effectors functions both of HLA class I and class II restricted T cell responses to HCV in the peripheral blood and, when possible, in the liver;
2) the quantitative (ELISA) and qualitative (neutralisation) aspects of the serum antibody responses to HCV.

The foregoing studies will lead to the identification of amino acid sequences (epitopes) within the various HCV antigens that are responsible for T and Bcell responses during acute and chronic HCV infection, and will establish the relationship between these responses and viral clearance and disease activity. Furthemore, we will gain knowledge on the role played by viral sequence variabil in viral persistence and disease pathogenesis. In conclusion, this is a proposal to characterize the humoral and cellular immune response to all of the known HCV-encoded antigens in an effort to delineate the factors potentially involved in viral clearance and liver disease. Characterization of the immune responses the various HCV antigens will hopefully provide the conceptual framework for the design of effective preventive strategies against HCV infection.


CSC - Cost-sharing contracts


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The Provost Fellows and Scholars of the Holy and Undivided Trinity of QueenElizabeth near Dublin hereinafter TCD

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