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@ARTICLE{Mehnert:304846,
      author       = {A.-K. Mehnert and S. Stegmaier$^*$ and C. Ramirez Alvarez
                      and E. Toprak and V. Goncalves Magalhaes$^*$ and C.
                      Siebenkotten and J. Hu and A. L. Costa and D. Kirrmaier$^*$
                      and M. Knop$^*$ and X. Wu and T. Tubiana and C. Herrmann and
                      M. Binder$^*$ and V. L. Dao Thi},
      title        = {{T}he hepatitis {E} virus capsid protein {ORF}2 counteracts
                      cell-intrinsic antiviral responses to enable persistent
                      replication in cell culture.},
      journal      = {PLoS pathogens},
      volume       = {21},
      number       = {9},
      issn         = {1553-7366},
      address      = {Lawrence, Kan.},
      publisher    = {PLoS},
      reportid     = {DKFZ-2025-01952},
      pages        = {e1013516},
      year         = {2025},
      note         = {#EA:D430#},
      abstract     = {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 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.},
      cin          = {D430 / A260},
      ddc          = {610},
      cid          = {I:(DE-He78)D430-20160331 / I:(DE-He78)A260-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40982567},
      doi          = {10.1371/journal.ppat.1013516},
      url          = {https://inrepo02.dkfz.de/record/304846},
}