Heterologous Immunity and Hepatitis C Virus: Impact on Natural Infection, Pathogenesis and Vaccine Design ^†

Abstract

Chronic infection with the hepatitis C virus (HCV) afflicts 1%–3% of the world’s population and can lead to serious and late-stage liver diseases. Developing a vaccine for HCV is challenging because the correlates of protection are uncertain. Host immune responses play an important role in the outcome of infection with HCV. They can lead to viral clearance and a positive outcome, or progression and severity of the chronic disease. Studies of natural immunity to HCV in humans have resulted in many enigmas. Extensive research in the past >25 years into understanding the immune responses against HCV have still resulted in many unanswered questions, implicating the role of unknown factors and events. Human beings are not immunologically naïve because they are continually exposed to various environmental microbes and antigens, creating large populations of memory T and B cells. This pool of memory T and B cells can cross-react against a new pathogen in an individual and thereby influence the outcome of the new infection. In our recent studies, we made the surprising discovery that peptides derived from structural and non-structural proteins of HCV have substantial amino acid sequence homologies with various proteins of adenoviruses, and that immunizing mice with a non-replicating, non-recombinant adenovirus (Ad) vector leads to induction of a robust cross-reactive cellular and humoral response against various HCV antigens. We also extended this observation to show that recombinant adenoviruses containing antigens from unrelated pathogens also possess the ability to induce cross-reactive immune responses against HCV antigens along with the induction of transgene antigen-specific immunity. This cross-reactive/heterologous immunity can a) accommodate the development of dual-pathogen vaccines, b) play an important role in the natural course of HCV infection, and c) provide a plausible answer to many unexplained questions regarding immunity to HCV.