The enterically transmitted hepatitis E virus (HEV) infects ~20 million people annually. HEV infection is usually self-resolving but can persist in individuals with a weakened immune system and result in fast progression into liver cirrhosis. HEV encodes a single capsid protein ORF2. Nonetheless, recent studies show that most ORF2 proteins released from HEV-infected cells are not associated with virus particles. The exact role(s) of the secreted ORF2 (ORF2s) plays is poorly understood, which hampers our understanding of HEV infection and pathogenesis. Our recently published work demonstrated that ORF2s and the capsid are two different translation products. A signal sequence unique to ORF2s directs its secretion via the secretory pathway, where as a conserved, but previously unrecognized, internal start codon is responsible for translation of the capsid- associated ORF2 (ORF2c). We further found that ORF2s exists as a glycosylated dimer with substantial antigenic overlap with the virion, and purified ORF2s was able to inhibit antibody-mediated neutralization of HEV. Based on these data, we hypothesize that ORF2s acts as a decoy to evade the host antibody response during HEV infection. Our long-term goal is to better understand how ORF2s modulates HEV infection and host immunity and whether it contributes to pathogenesis. The objectives of this project are to use an established rat model to test the in vivo role(s) of ORF2s in HEV infection.
Aim 1 will determine if eliminating ORF2s expression alters host antibody responses and the course of acute HEV infection.
Aim 2 will determine if serum ORF2s interferes with antibody therapy of chronic HEV infection, and if so whether the effectiveness of antibody therapy will be improved by using antibodies that target ORF2c but not ORF2s. The concept that ORF2S functions as an immunological decoy is novel and may have important implications for HEV immune evasion and persistence. The expected outcomes will fill a significant gap in our understanding of the role of secreted ORF2 in the HEV life cycle and pathogenesis with the potential for more targeted therapies where no cure currently exists.
HEV is a leading cause of acute hepatitis worldwide and is able to persist in immunocompromised patients resulting in increased risk of severe liver diseases. The project will investigate the role of the secreted viral ORF2 capsid protein in the virus life cycle and immune evasion in a rat model. The study will provide novel insight into the mechanism of HEV infection and persistence.