Hepatitis C virus (HCV) causes chronic liver disease worldwide. HCV Core protein (Core) forms the viral capsid and is crucial for HCV pathogenesis and HCV-induced hepatocellular carcinoma, through its interaction with the host factor proteasome activator PA28γ. Here, using BD-PowerBlot high-throughput Western array, we attempt to further investigate HCV pathogenesis by comparing the protein levels in liver samples from Core-transgenic mice with or without the knockout of PA28γ expression (abbreviated PA28γ(-/-)CoreTG and CoreTG, respectively) against the wild-type (WT). The differentially expressed proteins integrated into the human interactome were shown to participate in compact and well-connected cellular networks. Functional analysis of the interaction networks using a newly developed data warehouse system highlighted cellular pathways associated with vesicular transport, immune system, cellular adhesion, and cell growth and death among others that were prominently influenced by Core and PA28γ in HCV infection. Follow-up assays with in vitro HCV cell culture systems validated VTI1A, a vesicular transport associated factor, which was upregulated in CoreTG but not in PA28γ(-/-)CoreTG, as a novel regulator of HCV release but not replication. Our analysis provided novel insights into the Core-PA28γ interplay in HCV pathogenesis and identified potential targets for better anti-HCV therapy and potentially novel biomarkers of HCV infection.