HCV Nonstructural Proteins and Host Protein Secretion

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Hepatitis C virus (HCV) is one of the leading causes of liver cancer worldwide. Studies on HCV replication have been hampered by the lack of a convenient animal model or a reliable tissue culture system to propagate the virus. Investigators have focused on expression of HCV genes for functional and structural studies Most of the HCV non- structural proteins examined so far have been localized to the endoplasmic reticulum (ER). It is assumed therefore that expression of HCV NS4A/B precursor proteins results in the swelling of ER-like compartments and inhibits protein traffic between ER and Golgi apparatus. Thus, it is likely that HCV/NS4A/B o=precursor proteins inhibit cellular secretory pathway and modify intracellular compartments to form viral RNA replication complexes. In this proposal, the nature of the swollen intracellular compartments and their relationship to the HCV NS4A/B precursor proteins will be investigated. The ability of other HCV non-structural proteins (NS2/3/4A, NS4B/5A, NS4B/5A, NS4A and NS5B) to inhibit protein traffic will also be examined. Using MHC class I molecules, the specificity of this inhibition by HCV proteins will be tested. Similar studies will be done with homologous proteins of BVDV, a flavivirus that can be conveniently and safely be grown in tissue culture. Information gained from these studies will be useful in the selection of inhibitors or pathogenesis.