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The replication of herpesviruses requires manipulation of cell signaling pathways. Notably, CREB, a factor involved in the regulation of several cellular processes, is activated upon infection of T cells with VZV. Here, we report that VZV infection also induced CREB phosphorylation in fibroblasts and that XX-650-23, a newly identified inhibitor of the phosphorylated-CREB (pCREB) interaction with p300\/CBP, restricted cell-cell spread of VZV<jats:italic>in vitro<\/jats:italic>. CREB phosphorylation did not require the viral open reading frame 47 (ORF47) and ORF66 kinases encoded by VZV. Evaluating the biological relevance of these observations during VZV infection of human skin xenografts in the SCID mouse model of VZV pathogenesis showed both that pCREB was upregulated in infected skin and that treatment with XX-650-23 reduced infectious-virus production and limited lesion formation compared to treatment with a vehicle control. Thus, processes of CREB activation and p300\/CBP binding are important for VZV skin infection and may be targeted for antiviral drug development.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>Varicella-zoster virus (VZV) is a common pathogen that causes chicken pox and shingles. As with all herpesviruses, the infection is acquired for life, and the virus can periodically reactivate from latency. Although VZV infection is usually benign with few or no deleterious consequences, infection can be life threatening in immunocompromised patients. Otherwise healthy elderly individuals who develop zoster as a consequence of viral reactivation are at risk for postherpetic neuralgia (PHN), a painful and long-lasting complication. Current vaccines use a live attenuated virus that is usually safe but cannot be given to many immunodeficient patients and retains the capacity to establish latency and reactivate, causing zoster. Antiviral drugs are effective against severe VZV infections but have little impact on PHN. A better understanding of virus-host cell interactions is relevant for developing improved therapies to safely interfere with cellular processes that are crucial for VZV pathogenesis.<\/jats:p>","DOI":"10.1128\/jvi.00920-16","type":"journal-article","created":{"date-parts":[[2016,7,21]],"date-time":"2016-07-21T02:58:58Z","timestamp":1469069938000},"page":"8686-8697","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":16,"title":["Varicella-Zoster Virus Activates CREB, and Inhibition of the pCREB-p300\/CBP Interaction Inhibits Viral Replication<i>In Vitro<\/i>and Skin Pathogenesis<i>In Vivo<\/i>"],"prefix":"10.1128","volume":"90","author":[{"given":"Sylvie","family":"Fran\u00e7ois","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nandini","family":"Sen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Mitton","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA"},{"name":"Division of Hematology\/Oncology, Stanford University School of Medicine, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangshu","family":"Xiao","sequence":"additional","affiliation":[{"name":"The Knight Cancer Institute, Department of Physiology and Pharmacology, Oregon Health and Sciences University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen M.","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA"},{"name":"Division of Hematology\/Oncology, Stanford University School of Medicine, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Arvin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA"},{"name":"Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"2015","volume-title":"Fields virology","author":"Arvin A","year":"2013","unstructured":"Arvin A, Gliden D. 2013. 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