Evolutionary modeling reveals enhanced mutational flexibility of HCV subtype 1b compared with 1a

Hepatitis C virus (HCV) is a leading cause of liver-associated disease and liver cancer Of the major HCV subtypes, patients infected with subtype 1b have been associated with having a higher risk of developing chronic infection and hepatocellular carcinoma. However, underlying reasons for this increased disease severity remain unknown. Here, we provide an evolutionary rationale, based on a comparative study of fitness landscape and in-host evolutionary models of the E2 glycoprotein of HCV subtypes 1a and 1b. Our analysis demonstrates that a higher chronicity rate of 1b may be attributed to lower fitness constraints, enabling 1b viruses to more easily escape antibody responses. More generally, our results suggest that differences in evolutionary constraints between HCV subtypes may be an important factor in mediating distinct disease outcomes. Our analysis also identifies antibodies that appear escape-resistant against both subtypes 1a and 1b, providing directions for designing HCV vaccines having cross-subtype protection.

Automated summary

This study provides a comparative analysis of evolutionary models of HCV subtype 1b, revealing a higher chronic infection rate due to lower fitness constraints and easier escape from antibody responses compared to subtype 1a. The study also identifies antibodies that are escape-resistant against both subtypes, offering directions for developing HCV vaccines with cross-subtype protection.