{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T03:26:48Z","timestamp":1791343608589,"version":"4.3.1"},"reference-count":65,"publisher":"Rockefeller University Press","issue":"4","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1999,2,15]]},"abstract":"<jats:p>Mechanisms responsible for neuroattenuation of herpes simplex virus (HSV) have been defined previously by studies of mutant viruses in cultured cells. The hypothesis that null mutations in host genes can override the attenuated phenotype of null mutations in certain viral genes was tested. Mutants such as those in infected cell protein (ICP) 0, thymidine kinase, ribonucleotide reductase, virion host shutoff, and ICP34.5 are reduced in their capacity to replicate in nondividing cells in culture and in vivo. The replication of these viruses was examined in eyes and trigeminal ganglia for 1\u20137 d after corneal inoculation in mice with null mutations (\u2212\/\u2212) in interferon receptors (IFNR) for type I IFNs (IFN-\u03b1\/\u03b2R), type II IFN (IFN-\u03b3R), and both type I and type II IFNs (IFN-\u03b1\/\u03b2\/\u03b3R). Viral titers in eyes and ganglia of IFN-\u03b3R\u2212\/\u2212 mice were not significantly different from congenic controls. However, in IFN-\u03b1\/\u03b2R\u2212\/\u2212 or IFN-\u03b1\/\u03b2\/\u03b3R\u2212\/\u2212 mice, growth of all mutants, including those with significantly impaired growth in cell culture, was enhanced by up to 1,000-fold in eyes and trigeminal ganglia. Blepharitis and clinical signs of infection were evident in IFN-\u03b1\/\u03b2R\u2212\/\u2212 and IFN-\u03b1\/\u03b2\/\u03b3R\u2212\/\u2212 but not control mice for all viruses. Also, IFNs were shown to significantly reduce productive infection of, and spread from intact, but not scarified, corneas. Particularly striking was restoration of near-normal trigeminal ganglion replication and neurovirulence of an ICP34.5 mutant in IFN-\u03b1\/\u03b2R\u2212\/\u2212 mice. These data show that IFNs play a major role in limiting mutant and wild-type HSV replication in the cornea and in the nervous system. In addition, the in vivo target of ICP34.5 may be host IFN responses. These experiments demonstrate an unsuspected role for host factors in defining the phenotypes of some HSV mutants in vivo. The phenotypes of mutant viruses therefore cannot be interpreted based solely upon studies in cell culture but must be considered carefully in the context of host factors that may define the in vivo phenotype.<\/jats:p>","DOI":"10.1084\/jem.189.4.663","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:49:30Z","timestamp":1027702170000},"page":"663-672","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":292,"title":["Interferons Regulate the Phenotype of \u2009Wild-type and Mutant Herpes Simplex Viruses In Vivo"],"prefix":"10.1084","volume":"189","author":[{"given":"David A.","family":"Leib","sequence":"first","affiliation":[{"name":"From the *Departments of Ophthalmology and Visual Sciences and the \u2021Department of Molecular Microbiology, the \u00a7Center for Immunology, and the \u2016Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110"},{"name":"From the *Departments of Ophthalmology and Visual Sciences and the \u2021Department of Molecular Microbiology, the \u00a7Center for Immunology, and the \u2016Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travis E.","family":"Harrison","sequence":"additional","affiliation":[{"name":"From the *Departments of Ophthalmology and Visual Sciences and the \u2021Department of Molecular Microbiology, the \u00a7Center for Immunology, and the \u2016Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen M.","family":"Laslo","sequence":"additional","affiliation":[{"name":"From the *Departments of Ophthalmology and Visual Sciences and the \u2021Department of Molecular Microbiology, the \u00a7Center for Immunology, and the \u2016Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Machalek","sequence":"additional","affiliation":[{"name":"From the *Departments of Ophthalmology and Visual Sciences and the \u2021Department of Molecular Microbiology, the \u00a7Center for Immunology, and the \u2016Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel J.","family":"Moorman","sequence":"additional","affiliation":[{"name":"From the *Departments of Ophthalmology and Visual Sciences and the \u2021Department of Molecular Microbiology, the \u00a7Center for Immunology, and the \u2016Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herbert W.","family":"Virgin","sequence":"additional","affiliation":[{"name":"From the *Departments of Ophthalmology and Visual Sciences and the \u2021Department of Molecular Microbiology, the \u00a7Center for Immunology, and the \u2016Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110"},{"name":"From the *Departments of Ophthalmology and Visual Sciences and the \u2021Department of Molecular Microbiology, the \u00a7Center for Immunology, and the \u2016Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110"},{"name":"From the *Departments of Ophthalmology and Visual Sciences and the \u2021Department of Molecular Microbiology, the \u00a7Center for Immunology, and the \u2016Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 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