{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T14:17:09Z","timestamp":1776262629606,"version":"3.50.1"},"reference-count":83,"publisher":"American Society for Microbiology","issue":"17","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2015,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Varicella-zoster virus (VZV) causes chickenpox upon primary infection and establishes latency in ganglia. Reactivation from latency causes herpes zoster, which may be complicated by postherpetic neuralgia. Innate immunity mediated by interferon and proinflammatory cytokines represents the first line of immune defense upon infection and reactivation. VZV is known to interfere with multiple innate immune signaling pathways, including the central transcription factor NF-\u03baB. However, the role of these inhibitory mechanisms\n            <jats:italic>in vivo<\/jats:italic>\n            is unknown. Simian varicella virus (SVV) infection of rhesus macaques recapitulates key aspects of VZV pathogenesis, and this model thus permits examination of the role of immune evasion mechanisms\n            <jats:italic>in vivo<\/jats:italic>\n            . Here, we compare SVV and VZV with respect to interference with NF-\u03baB activation. We demonstrate that both viruses prevent ubiquitination of the NF-\u03baB inhibitor I\u03baB\u03b1, whereas SVV additionally prevents I\u03baB\u03b1 phosphorylation. We show that the ORF61 proteins of VZV and SVV are sufficient to prevent I\u03baB\u03b1 ubiquitination upon ectopic expression. We further demonstrate that SVV ORF61 interacts with \u03b2-TrCP, a subunit of the SCF ubiquitin ligase complex that mediates the degradation of I\u03baB\u03b1. This interaction seems to inactivate SCF-mediated protein degradation in general, since the unrelated \u03b2-TrCP target Snail is also stabilized by ORF61. In addition to ORF61, SVV seems to encode additional inhibitors of the NF-\u03baB pathway, since SVV with ORF61 deleted still prevented I\u03baB\u03b1 phosphorylation and degradation. Taken together, our data demonstrate that SVV interferes with tumor necrosis factor alpha (TNF-\u03b1)-induced NF-\u03baB activation at multiple levels, which is consistent with the importance of these countermechanisms for varicella virus infection.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            The role of innate immunity during the establishment of primary infection, latency, and reactivation by varicella-zoster virus (VZV) is incompletely understood. Since infection of rhesus macaques by simian varicella virus (SVV) is used as an animal model of VZV infection, we characterized the molecular mechanism by which SVV interferes with innate immune activation. Specifically, we studied how SVV prevents activation of the transcription factor NF-\u03baB, a central factor in eliciting proinflammatory responses. The identification of molecular mechanisms that counteract innate immunity might ultimately lead to better vaccines and treatments for VZV, since overcoming these mechanisms, either by small-molecule inhibition or by genetic modification of vaccine strains, is expected to reduce the pathogenic potential of VZV. Moreover, using SVV infection of rhesus macaques, it will be possible to study how increasing the vulnerability of varicella viruses to innate immunity will impact viral pathogenesis.\n          <\/jats:p>","DOI":"10.1128\/jvi.01149-15","type":"journal-article","created":{"date-parts":[[2015,6,18]],"date-time":"2015-06-18T02:46:26Z","timestamp":1434595586000},"page":"8687-8700","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":32,"title":["The ORF61 Protein Encoded by Simian Varicella Virus and Varicella-Zoster Virus Inhibits NF-\u03baB Signaling by Interfering with I\u03baB\u03b1 Degradation"],"prefix":"10.1128","volume":"89","author":[{"given":"Travis","family":"Whitmer","sequence":"first","affiliation":[{"name":"Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA"}]},{"given":"Daniel","family":"Malouli","sequence":"additional","affiliation":[{"name":"Vaccine and Gene 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