The hepatitis E virus capsid protein ORF2 counteracts cell-intrinsic antiviral responses to enable persistence in hepatocytes
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Hepatitis E virus (HEV) is a significant human pathogen causing both acute and chronic infections worldwide. The cell-intrinsic antiviral response serves as the initial defense against viruses and has been shown to be activated upon HEV infection. HEV can replicate in the presence of this response, but the underlying mechanisms remain poorly understood.
Here, we investigated the role of HEV structural proteins ORF2 and ORF3 in immunocompetent cells. Mechanistically, we found that ectopic ORF2, but not ORF3, interfered with inflammatory signaling pathways as well as with antiviral signaling downstream of pattern recognition receptors. The latter was at least in part mediated through direct interaction with the central adaptor protein TANK binding kinase 1. In addition, we discovered a protective mechanism mediated by ORF2 that shielded viral replication from antiviral effectors. Using single-cell RNA-sequencing, we confirmed that the ORF2-mediated antagonism in infected cells resulted in dampened antiviral responses in both HEV-infected and bystander cells. As a consequence, we found that early in the infection process, the progression of authentic HEV infection relied on the presence of ORF2, facilitating a balance between viral replication and the antiviral response within immunocompetent cells. Altogether, our findings shed new light on the multifaceted role of ORF2 in the HEV life cycle and improve our understanding of the determinants that may contribute to HEV persistence.
Significance statement
Hepatitis E virus (HEV) is an important yet often underestimated pathogen. Depending on the genotype, HEV infections can progress to chronicity, but the underlying mechanisms remain poorly understood. To gain insight into potential determinants, we investigated how HEV evades the body’s first line of defense, the cell-intrinsic antiviral response. We discovered that the HEV capsid protein ORF2 is crucial in limiting this response by interfering with antiviral signaling pathways and shielding viral replication from immune effectors. This balance between viral replication and the antiviral response contributes to persistent HEV infection in immunocompetent cells. Our findings reveal a new role for the HEV capsid protein in the viral life cycle and highlight it as an important target for novel therapeutic approaches.
