CD4+ T cell failure in chronic HCV infection

• Applicant: Dr. Nasser Semmo
• Subject Area: Gastroenterology
• Term: from 2007 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 34671243

Hepatitis C virus (HCV) infection is a major cause of liver damage, with virusinduced end-stage disease such as liver cirrhosis and hepatocellular carcinoma resulting in a high rate of morbidity and mortality worldwide. There is currently no vaccine available and treatment options for those chronically infected are limited, with resistance to anti-viral therapy in a large proportion of infected patients. Novel strategies for the prevention and treatment of HCV are therefore urgently needed. There is now considerable evidence that CD4+ T cell responses to HCV play an important role in the outcome of infection. Several groups have demonstrated that during chronic HCV infection, HCV-specific CD4+ T cell responses are weak or absent. However, the functional status of HCV-specific CD4+ve T cells in persistent infection is poorly understood and it may be necessary to use various techniques in their detection. In the last two years, using overlapping peptides, we have been able to identify HCV-specific CD4+ T cells in persistent infection that recognize the mainly conserved core region. These cells characteristically produce IFN-γ but not IL-2 and do not have the ability to proliferate (IFN-γ+/IL-2-/proliferationlo). To what extent such cells play a role in determining disease outcome and whether they can be modulated to prevent disease progression remain important questions, which we will attempt to address in this project. Overall, together with these and other previously shown data we hypothesize that HCV-specific CD4+ T cells are altered in terms of frequency, phenotype and function. It is therefore necessary to further characterize the phenotype (differentiation status) as well as the extent and magnitude of the function of HCV-specific CD4+ T cells in acute and chronic HCV infection and look whether there is a correlation with HCV-specific CD8+ T cells. This work will be of value in understanding the basic biology of immune responses against persistent viruses, and specifically will be of value in designing vaccines and therapeutic strategies in future.

• DFG Programme: Research Grants