There are more than 130 million people infected with Hepatitis C worldwide. The Hepatitis C virus (HCV) is an enveloped RNA virus targeting liver cells. HCV represents one of the most important pathogens of humans. It is still not clear how exactly viral entry proceeds. So far several receptors have been found to play a role in virus entry, among them CD81, SR-BI and Claudin-1. The recent finding of a negative regulator, EWI-2wint, further complicates the matter. This protein, which is an Nterminally processed variant of EWI-2, a direct interactor of CD81, blocks the binding of the HCV envelope proteins to the receptor CD81. Expression of EWI-2wint in cells susceptible to HCV leads to a reduced infection rate. The aim of the proposed project is to characterize the inhibiton of HCV infection by EWI-2wint. I have three specific objectives: One is to find the minimal region of EWI-2wint that is essential for its inhibitory effect. In addition, I will test whether soluble forms of EWI-2wint can act as inhibitors of infection. Another objective is the characterization of the interactions between the viral glycoproteins, CD81 and EWI-2 or EWI-2wint. The third objective is to identify the protease responsible for the cleavage of EWI-2 into EWI-2wint. The results of these experiments will help to understand the complex HCV infection mechanism and maybe also the basis for the hepatotropism of the virus, as this might be due to the absence of the specific inhibitor EWI-2wint. Expression analyses might also lead to a better understanding of the cellular role of the protease. Furthermore, an inhibiton achieved with soluble forms of EWI-2wint or the tracing of the inhibitory properties to a defined domain are an excellent starting point for the development of new therapeutic strategies.
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