Hepatitis C viral protein translation modulation

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The long-term goal of this research program is to study hepatitis C virus (HCV) protein translation. As an important step in virus lifecycle, HCV protein translation is primarily controlled by an internal ribosomal entry site (IRES) present in the 5'untranslated region (5'UTR). In addition, 3'UTR and nonstructural protein-5A (NS5A) have been shown to impact HCV protein translation. We have demonstrated that HCV NS5A inhibits HCV protein translation through binding to the poly-U/UC sequence in the 3'UTR. In addition, our ongoing research showed that a cellular kinase Akt3 is involved in modulating HCV protein translation. As such, the short-term goal of this proposal is to further characterize the molecular mechanisms by which HCV NS5A modulates HCV protein translation. We will test the hypothesis that HCV NS5A protein inhibits HCV protein translation through binding to HCV 3'UTR and through Akt3-mediated signal transduction pathways. Research will focus in three objectives. 1. Further characterize HCV 3'UTR binding and HCV protein translation modulation by NS5A. 2. Characterize how viral and cellular proteins modulate the effect of NS5A on HCV protein translation. 3. Study the impact of Akt3 on HCV protein translation modulation by HCV NS5A. This proposal will provide an excellent opportunity for the training of graduate students and undergraduate summer students in virology and molecular biology. The proposed research is very important because HCV is infecting up to 3% of the population. No vaccines are available and the efficacy of current anti-virals is far from satisfactory. Knowledge gained from this proposal may lead to new anti-viral development targeting HCV protein translation, NS5A RNA binding, NS5A phosphorylation, and/or Akt3. HCV has a homolog virus in domestic dogs (canine hepacivirus). HCV is also very similar to a bovine pathogen bovine viral diarrhea virus (BVDV). Therefore, this proposal will have important implications in the research of animal viruses.