Hepatitis C virus (HCV) chronically infects over 57 million individuals globally, contributing to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Although curative antiviral treatments exist, prior infection does not provide immunity, leading to high rates of reinfection and significant challenges to healthcare systems worldwide. A prophylactic vaccine for HCV would be essential to prevent transmission. However, because the virus’s species tropism is limited to humans and chimpanzees, it is difficult to study long-term pathogenesis, oncogenesis, and vaccine development. A mouse model of HCV infection would provide a transformative platform for research, albeit this is predicated upon a comprehensive understanding of mouse-specific barriers to HCV infection. Previous research has demonstrated that HCV induces the degradation of the antiviral signaling protein STAT2 in human cells by upregulating the E3 ubiquitin ligase PDLIM2. Whether this process occurs in mice, with self-evident implications for tropism, has not been addressed. We hypothesized that HCV replication in murine cells is prevented due to the virus’s inability to induce murine STAT2 degradation. In this thesis, I have conducted in silico analyses of both human and murine PDLIM2 and STAT2, comparing amino acid sequences, domain architecture, and tertiary structure. I have further generated a variety of in vitro tools to probe STAT2 stability during HCV infection in human cells, which I leverage to assess the prior phenotype. Lastly, I have generated an HCV-susceptible mouse strain expressing human STAT2 to assess the in vivo impact of this mechanism. This study fits into broader goals of the field to understand barriers to HCV infection in mice and to develop a genetically humanized mouse model that can support HCV.