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We hypothesized that Akt signaling induces the calcium responses and contributes to HSV entry. Exposure of human cervical and primary genital tract epithelial, neuronal, or keratinocyte cells to HSV serotype 2 resulted in rapid phosphorylation of Akt. Silencing of Akt with small interfering RNA prevented the calcium responses, blocked viral entry, and inhibited plaque formation by 90% compared to control siRNA. Susceptibility to infection was partially restored if Akt was reintroduced into silenced cells with an Akt\u2010expressing plasmid. HSV\u20102 variants deleted in glycoproteins B or D failed to induce Akt phosphorylation, and coimmunoprecipitation studies indicated that Akt interacts with glycoprotein B. Cell\u2010surface expression of Akt was rapidly induced in response to HSV exposure. Miltefosine (50 \u03bcM), a licensed drug that blocks Akt phosphorylation, inhibited HSV\u2010induced calcium release, viral entry, and plaque formation following infection with acyclovir\u2010sensitive and resistant clinical isolates. Miltefosine blocked amplification of HSV from explanted ganglia to epithelial cells; viral yields were significantly less in miltefosine compared to control\u2010treated cocultures (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.01). Together, these findings identify a novel role for Akt in viral entry, link Akt and calcium signaling, and suggest a new target for HSV treatment and suppression.\u2014 Cheshenko, N., Trepanier, J. B., Stefanidou, M., Buckley, N., Gonzalez, P., Jacobs, W., and Herold, B. C. HSV activates Akt to trigger calcium release and promote viral entry: novel candidate target for treatment and suppression.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    27, 2584\u20132599 (2013).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.12-220285","type":"journal-article","created":{"date-parts":[[2013,3,19]],"date-time":"2013-03-19T03:17:02Z","timestamp":1363663022000},"page":"2584-2599","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":93,"title":["HSV activates Akt to trigger calcium release and promote viral entry: novel candidate target for treatment and suppression"],"prefix":"10.1096","volume":"27","author":[{"given":"Natalia","family":"Cheshenko","sequence":"first","affiliation":[{"name":"Department of Pediatrics Albert Einstein College of Medicine Bronx New York USA"},{"name":"Department of Microbiology\u2010Immunology Albert Einstein College of Medicine Bronx New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janie B.","family":"Trepanier","sequence":"additional","affiliation":[{"name":"Department of Microbiology\u2010Immunology Albert Einstein College of Medicine Bronx New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Stefanidou","sequence":"additional","affiliation":[{"name":"Department of Microbiology\u2010Immunology Albert Einstein College of Medicine Bronx New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niall","family":"Buckley","sequence":"additional","affiliation":[{"name":"Department of Microbiology\u2010Immunology Albert Einstein College of Medicine Bronx New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Microbiology\u2010Immunology Albert Einstein College of Medicine Bronx New York USA"},{"name":"Howard Hughes Medical Institute; Albert Einstein College of Medicine Bronx New York USA"},{"name":"Millennium Institute on Immunology and Immunotherapy Pontificia Universidad Cat\u00f3lica de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Jacobs","sequence":"additional","affiliation":[{"name":"Department of Microbiology\u2010Immunology Albert Einstein College of Medicine Bronx New York USA"},{"name":"Department of Medicine Albert Einstein College of Medicine Bronx New York USA"},{"name":"Department of Genetics Albert Einstein College of Medicine Bronx New York USA"},{"name":"Howard Hughes Medical Institute; Albert Einstein College of Medicine Bronx New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betsy C.","family":"Herold","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Albert Einstein College of Medicine Bronx New York USA"},{"name":"Department of Microbiology\u2010Immunology Albert Einstein College of Medicine Bronx New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,3,18]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2011.420"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa035144"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1103151"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1586\/eri.09.34"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2004.00389.x"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-008-7570-z"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200301084"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e07-01-0062"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2008.10.005"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1102-e263"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0409657102"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(06)00122-9"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/371168a0"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600218"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.12.8271"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2008.10.006"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod57.4.847"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1086\/340512"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1995.9957"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.9.7563-7568.1998"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02029-09"},{"key":"e_1_2_7_23_1","doi-asserted-by":"crossref","first-page":"e27675","DOI":"10.1371\/journal.pone.0027675","article-title":"Bridging the gap between preclinical and clinical microbicide trials: blind evaluation of candidate gels in murine models of efficacy and safety","volume":"6","author":"Segarra T. 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