The enterically transmitted hepatitis E virus (HEV) has a unique dual life style: while shed as non-enveloped virions in feces, it circulates in the bloodstream as quasi-enveloped virions (eHEV). While the quasi- envelopment provides effective protection for free virions against antibodies, our new data suggest that this strategy is not perfect because antibodies are able to neutralize eHEV intracellularly and limit virus spread. In addition, large quantities of viral RNA-free capsid antigen (free antigen) are present both in the supernatant of HEV-infected cells and in the sera of HEV-infected humans and macaques for reasons that are not under- stood. Our preliminary data suggest that the HEV free antigen is produced as a result from translation initiated at an alternative start codon of the capsid gene and is able to reduce antibody-mediated neutralization of HEV. However, it is not essential for the HEV life cycle. We hypothesize that HEV free antigen serves as an antigen decoy to further dampen the host antibody response during HEV infection. Our long-term goal is to better un- derstand the mechanisms by which HEV free Ag modulates host immunity and contributes to HEV pathogene- sis. The objectives of this project are to elucidate the mechanism(s) underlying the bulk accumulation of HEV free antigen (Aim 1) and to determine if free antigen functions as an antigen decoy (Aim 2). The completion of this study will fill a significant gap in our understanding of the life cycle and pathogenesis of HEV.
HEV is a leading cause of acute hepatitis worldwide and is able to persist in immunocompromised patients re- sulting in increased risk of severe liver diseases. Currently there are no FDA-approved diagnostic or treat- ments for HEV infections. The project seeks to understand the underrated role(s) of non-virion-associated cap- sid antigen that is present in a large excess to virions in the serum of infected persons. We will explore the mechanism underlying its bulk production and its potential role as an antigen decoy for immune evasion.
| Yin, Xin; Ying, Dong; Lhomme, Sébastien et al. (2018) Origin, antigenicity, and function of a secreted form of ORF2 in hepatitis E virus infection. Proc Natl Acad Sci U S A 115:4773-4778 |
