Time-Resolved Proteomic Analysis of Hepatitis B Virus Infection

Hepatitis B virus (HBV) infection is a major cause of chronic liver disease and hepatocellular carcinoma, yet its impact on host proteome dynamics during early infection remains poorly defined. Here, we performed time-resolved label-free quantitative (LFQ) proteomics to characterize the host response to HBV infection in human HepG2 hepatoma cells. Across five time points spanning the first 3 weeks of infection, we quantified 5365 unique proteins, including two HBV proteins (C/preC-derived and S), revealing subtle yet coordinated changes in the hepatocellular proteome. Early infection was characterized by selective alterations in cytoskeletal organization, extracellular matrix components, and focal adhesion pathways, alongside enrichment of complement-associated proteins. Notably, we identified a transient, specific increase in the abundance of complement component C5 without a corresponding change in C3, indicating differential regulation of complement pathway members during infection. These findings define a temporally resolved proteomic landscape of HBV–host interactions and uncover previously underappreciated complement dynamics consistent with a selective and restrained host response. Together, our results provide a framework for mechanistic studies of early viral infection and host adaptation.