Grant: Project Grant

RNA viruses are a major global concern for both human and animal health. HCV has infected approximately 130 million people and 71 million are chronic carriers. If left untreated, a significant number will develop cirrhosis and/or liver cancer. There are 50-100 million cases of Dengue fever annually, and the recent Zika virus outbreak emphasizes the human and economic cost of viral infections. This grant focuses on basic mechanisms that viruses use to replicate and assemble, and escape from the cells innate immune system. We first proposed and demonstrated that HCV steals a component of the cell nucleus, called the nuclear pore complex (NPC), to create a protected area in the cytoplasm where the virus replicates. This appears to be a general characteristic of positive strand RNA viruses as we have shown this for HCV, HAV, Dengue, and Zika viruses. We will study the details of how HCV uses its ability to move the NPC from nucleus to the cytoplasmic factory to replicate and assemble in a protected site. We plan to extend our studies to additional RNA viruses (Zika, Dengue and Rotavirus) to show that hijacking the NPC is a common mechanism used by many RNA viruses to escape the innate immune system. Finally, we plan to examine how viruses control host gene expression using HCV as an example. It is becoming clear that "junk DNA" in humans often has regulatory functions. Some "junk DNA" expresses specific RNAs that associate with the host cell DNA and lead to changes in gene expression. We will determine whether the association of HCV RNA with host DNA impacts the regulation of the innate immune response. How viruses regulate host gene expression is a key unanswered question in virology.