Identification and characterization of positive regulators governing hepatitis C virus host tropism

Abstract

Hepatitis C virus (HCV) continues to affect millions of lives worldwide. Although the advent of highly effective direct-acting antivirals (DAAs) has revolutionized clinical management of chronic hepatitis C as the great majority of affective individuals can be cured of their infection, DAAs are very expensive and HCV transmission remains high in most countries, including the United States. Therefore, the development of a vaccine is essential to contain HCV transmission more efficiently. However, systematic testing of vaccine candidates is significantly hindered because HCV can only infect humans and chimpanzees. Understanding HCV’s limited host tropism is critical towards the development of an animal model for HCV infection. This study hypothesizes that human-specific host factors exist which are not expressed in murine cells or whose murine orthologues are not functional, that can boost HCV permissiveness in murine cells. Prior studies have implicated Tripartite Motif Containing 26 (TRIM26), and cyclophilin A (CypA) to modulate HCV replication efficiency across different species. However, our results do not confirm that their expression augments HCV infection in murine cells. By utilizing the human ORFeome library, a gain of function screen was conducted to identify additional human factors that augment HCV infection in murine cells. In parallel, transgenic mice were generated to express human factors and infected with HCV to assess the effect of these human factors on HCV infection in vivo. Identifying and characterizing positive regulators that govern HCV host tropism will lead to the construction of an HCV-susceptible mouse that can be used for further research which will pave the way for the development of a vaccine for HCV.