{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:48:34Z","timestamp":1787320114801,"version":"build-2736575974"},"reference-count":47,"publisher":"American Society for Microbiology","issue":"19","license":[{"start":{"date-parts":[[2016,9,12]],"date-time":"2016-09-12T00:00:00Z","timestamp":1473638400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2016,10,1]],"date-time":"2016-10-01T00:00:00Z","timestamp":1475280000000},"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":[[2016,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    In chronic hepatitis B (CHB), failure to control hepatitis B virus (HBV) is associated with T cell dysfunction. HBV transgenic mice mirror many features of the human disease, including T cell unresponsiveness, and thus represent an appropriate model in which to test novel therapeutic strategies. To date, the tolerant state of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells in these animals could be altered only by strong immunogens or by immunization with HBV antigen-pulsed dendritic cells; however, the effectors induced were unable to suppress viral gene expression or replication. Because of the known stimulatory properties of alpha interferon (IFN-\u03b1) and interleukin-15 (IL-15), this study explored the therapeutic potential of liver-directed gene transfer of these cytokines in a murine model of CHB using adeno-associated virus (AAV) delivery. This combination not only resulted in a reduction in the viral load in the liver and the induction of an antibody response but also gave rise to functional and specific CD8\n                    <jats:sup>+<\/jats:sup>\n                    immunity. Furthermore, when splenic and intrahepatic lymphocytes from IFN-\u03b1- and IL-15-treated animals were transferred to new HBV carriers, partial antiviral immunity was achieved. In contrast to previous observations made using either cytokine alone, markedly attenuated PD-L1 induction in hepatic tissue was observed upon coadministration. An initial study with CHB patient samples also gave promising results. Hence, we demonstrated synergy between two stimulating cytokines, IL-15 and IFN-\u03b1, which, given together, constitute a potent approach to significantly enhance the CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell response in a state of immune hyporesponsiveness. Such an approach may be useful for treating chronic viral infections and neoplastic conditions.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    With 350 million people affected worldwide and 600,000 annual deaths due to HBV-induced liver cirrhosis and\/or hepatocellular carcinoma, chronic hepatitis B (CHB) is a major health problem. However, current treatment options are costly and not very effective and\/or need to be administered for life. The unprecedented efficacy of the strategy described in our paper may offer an alternative and is relevant for a broad spectrum of readers because of its clear translational importance to other chronic viral infections in which a hyporesponsive antigen-specific T cell repertoire prevents clearance of the pathogen.\n                  <\/jats:p>","DOI":"10.1128\/jvi.01030-16","type":"journal-article","created":{"date-parts":[[2016,7,20]],"date-time":"2016-07-20T22:58:58Z","timestamp":1469055538000},"page":"8563-8574","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":17,"title":["Complementary Effects of Interleukin-15 and Alpha Interferon Induce Immunity in Hepatitis B Virus Transgenic Mice"],"prefix":"10.1128","volume":"90","author":[{"given":"Marianna","family":"Di Scala","sequence":"first","affiliation":[{"name":"Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), 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and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Olag\u00fce","sequence":"additional","affiliation":[{"name":"Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Navarra (IdisNA), Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Africa","family":"Vales","sequence":"additional","affiliation":[{"name":"Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Navarra (IdisNA), Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Galarraga","sequence":"additional","affiliation":[{"name":"Imaging Unit and Cancer Imaging Laboratory, CIMA, Pamplona, 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