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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 roles of the structural proteins ORF2 and ORF3 in the cell-intrinsic antiviral response to HEV infection. Mechanistically, we validated that ectopic ORF2, but not ORF3, interfered with antiviral and inflammatory signaling downstream of pattern recognition receptors, in part through interaction with the central adaptor protein TANK binding kinase 1. In the full-length viral context, ORF2 contributed to a reduced antiviral response and consequently, more efficient viral replication. 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 presence of ORF2 in infected cells dampened antiviral responses in both actively infected cells and bystanders. 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. 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 contribute to persistent HEV replication in cell culture.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013516","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T17:47:16Z","timestamp":1758563236000},"page":"e1013516","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["The hepatitis E virus capsid protein ORF2 counteracts cell-intrinsic antiviral responses to enable persistent replication in cell culture"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8935-2894","authenticated-orcid":true,"given":"Ann-Kathrin","family":"Mehnert","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Stegmaier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Ramirez Alvarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elif","family":"Toprak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir Gon\u00e7alves","family":"Magalh\u00e3es","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Siebenkotten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jungen","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana 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Loan","family":"Dao Thi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,9,22]]},"reference":[{"issue":"7","key":"ppat.1013516.ref001","doi-asserted-by":"crossref","first-page":"617","DOI":"10.3390\/v11070617","article-title":"The Clinical Perspective on Hepatitis E","volume":"11","author":"T Horvatits","year":"2019","journal-title":"Viruses"},{"issue":"2","key":"ppat.1013516.ref002","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/nrgastro.2017.150","article-title":"Hepatitis E virus: advances and challenges","volume":"15","author":"I Nimgaonkar","year":"2018","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"9","key":"ppat.1013516.ref003","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/s41579-023-00889-z","article-title":"Cell entry and release of quasi-enveloped human hepatitis viruses","volume":"21","author":"A Das","year":"2023","journal-title":"Nat Rev Microbiol"},{"issue":"8","key":"ppat.1013516.ref004","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1010798","article-title":"An Arginine-Rich Motif in the ORF2 capsid protein regulates the hepatitis E virus lifecycle and interactions with the host cell","volume":"18","author":"K Hervouet","year":"2022","journal-title":"PLoS Pathog"},{"issue":"18","key":"ppat.1013516.ref005","doi-asserted-by":"crossref","first-page":"4773","DOI":"10.1073\/pnas.1721345115","article-title":"Origin, antigenicity, and function of a secreted form of ORF2 in hepatitis E virus infection","volume":"115","author":"X Yin","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"ppat.1013516.ref006","doi-asserted-by":"crossref","DOI":"10.1053\/j.gastro.2017.09.020","article-title":"Hepatitis E Virus Lifecycle and Identification of 3 Forms of the ORF2 Capsid Protein","volume":"154","author":"C Montpellier","year":"2018","journal-title":"Gastroenterology"},{"issue":"1","key":"ppat.1013516.ref007","doi-asserted-by":"crossref","first-page":"6243","DOI":"10.1038\/s41598-019-42737-2","article-title":"New insights into the ORF2 capsid protein, a key player of the hepatitis E virus lifecycle","volume":"9","author":"M Ankavay","year":"2019","journal-title":"Sci Rep"},{"issue":"9","key":"ppat.1013516.ref008","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/s41577-020-0288-3","article-title":"RIG-I-like receptors: their regulation and roles in RNA sensing","volume":"20","author":"J Rehwinkel","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"ppat.1013516.ref009","doi-asserted-by":"crossref","first-page":"461","DOI":"10.3389\/fimmu.2014.00461","article-title":"Toll-like receptor signaling pathways","volume":"5","author":"T Kawasaki","year":"2014","journal-title":"Front 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Bagdassarian","year":"2018","journal-title":"Viruses"},{"key":"ppat.1013516.ref025","doi-asserted-by":"crossref","first-page":"656","DOI":"10.3389\/fmicb.2020.00656","article-title":"Hepatitis E Virus ORF2 Inhibits RIG-I Mediated Interferon Response","volume":"11","author":"S Hingane","year":"2020","journal-title":"Front Microbiol"},{"issue":"11","key":"ppat.1013516.ref026","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.3390\/v11111050","article-title":"The Capsid Protein of Hepatitis E Virus Inhibits Interferon Induction via Its N-terminal Arginine-Rich Motif","volume":"11","author":"S Lin","year":"2019","journal-title":"Viruses"},{"key":"ppat.1013516.ref027","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1471-2091-13-7","article-title":"The ORF2 glycoprotein of hepatitis E virus inhibits cellular NF-\u03baB activity by blocking ubiquitination mediated proteasomal degradation of I\u03baB\u03b1 in human hepatoma cells","volume":"13","author":"M Surjit","year":"2012","journal-title":"BMC Biochem"},{"issue":"5","key":"ppat.1013516.ref028","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1002\/hep.25530","article-title":"Suppression of interferon-\u03b1 signaling by hepatitis E virus","volume":"55","author":"C Dong","year":"2012","journal-title":"Hepatology"},{"key":"ppat.1013516.ref029","doi-asserted-by":"crossref","first-page":"27597","DOI":"10.1038\/srep27597","article-title":"The ORF3 Protein of Genotype 1 Hepatitis E Virus Suppresses TLR3-induced NF-\u03baB Signaling via TRADD and RIP1","volume":"6","author":"M He","year":"2016","journal-title":"Sci Rep"},{"issue":"1","key":"ppat.1013516.ref030","doi-asserted-by":"crossref","first-page":"8585","DOI":"10.1038\/s41598-018-26975-4","article-title":"HEV ORF3 downregulates TLR7 to inhibit the generation of type I interferon via impairment of multiple signaling pathways","volume":"8","author":"Q Lei","year":"2018","journal-title":"Sci 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Colasanti","year":"2023","journal-title":"J Hepatol"},{"issue":"6","key":"ppat.1013516.ref040","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","author":"A Liberzon","year":"2015","journal-title":"Cell Syst"},{"issue":"6","key":"ppat.1013516.ref041","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.coviro.2011.10.008","article-title":"Interferon-stimulated genes and their antiviral effector functions","volume":"1","author":"JW Schoggins","year":"2011","journal-title":"Curr Opin Virol"},{"issue":"7344","key":"ppat.1013516.ref042","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nature09907","article-title":"A diverse range of gene products are effectors of the type I interferon antiviral response","volume":"472","author":"JW 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