Abstract
Host immune responses play an important role in the outcome of infection with hepatitis C virus (HCV). They can lead to viral clearance and a positive outcome, or progression and severity of chronic disease. Extensive research in the past >25 years into understanding the immune responses against HCV have still resulted in many unanswered questions implicating a role for unknown factors and events. In our earlier studies, we made a 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 vector leads to induction of a robust cross-reactive cellular and humoral response against various HCV antigens. In this work, we further demonstrate antibody cross-reactivity between Ad and HCV in vivo. We also extend 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 immunity can (a) accommodate the making 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.
Highlights
Hepatitis C virus (HCV) is a serious human pathogen and worldwide, ~170 million people are chronically infected with hepatitis C virus (HCV) [1]
We examined whether mice immunized with recombinant adenoviruses that contain transgene antigens from HCV or unrelated pathogens such as Mycobacterium tuberculosis (Mtb), human immunodeficiency virus (HIV) and Ebola virus (EBOV), can induce cross-reactive humoral and cellular immunity against various HCV
Using high-throughput screening methods, our results demonstrated that individual recombinant adenovirus vectors (rAds) containing HCV-NS3, Mtb-Ag85B, HIV-gag, HIV-nef and EBOV-ZGP antigens, all induce cross-reactive humoral and cellular immune responses in mice against HCV-derived core, NS3 and NS5 antigens, in addition to the transgene antigen- specific responses
Summary
Hepatitis C virus (HCV) is a serious human pathogen and worldwide, ~170 million people are chronically infected with HCV [1]. We have been studying recombinant adenovirus vectors (rAds) that express various HCV antigens as a way to understand the generation of protective immune responses against HCV antigens in both humans (ex vivo) and mice (in vivo) for vaccine purposes [23,24,25,26,27] During these studies, we started to observe unusual cellular and humoral immunity against various HCV antigens even when we used replication-deficient, non-recombinant adenovirus vector (hu Ad5) not containing an HCV transgene, as controls for our recombinant Ads. After extensive studies, we confirmed robust amino acid homologies and immune cross-reactivity between various peptides from antigens derived from. Using high-throughput screening methods, our results demonstrated that individual rAds containing HCV-NS3, Mtb-Ag85B, HIV-gag, HIV-nef and EBOV-ZGP antigens, all induce cross-reactive humoral and cellular immune responses in mice against HCV-derived core, NS3 and NS5 antigens, in addition to the transgene antigen- specific responses
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