title: Complementary Effects of Interleukin-15 and Alpha Interferon Induce Immunity in Hepatitis B Virus Transgenic Mice.
abstract: 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(+) 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-α) 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(+) immunity. Furthermore, when splenic and intrahepatic lymphocytes from IFN-α- 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-α, which, given together, constitute a potent approach to significantly enhance the CD8(+) T cell response in a state of immune hyporesponsiveness. Such an approach may be useful for treating chronic viral infections and neoplastic conditions.
  
  
  
  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.
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain Instituto de Investigación Sanitaria de Navarra (IdisNA), Pamplona, Spain.
authors.forename: Marianna
authors.initials: M
authors.lastname: Di Scala
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Itziar
authors.initials: I
authors.lastname: Otano
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Gil-Fariña
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain.
authors.forename: Lucia
authors.initials: L
authors.lastname: Vanrell
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain.
authors.forename: Mirja
authors.initials: M
authors.lastname: Hommel
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain Instituto de Investigación Sanitaria de Navarra (IdisNA), Pamplona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Olagüe
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain Instituto de Investigación Sanitaria de Navarra (IdisNA), Pamplona, Spain.
authors.forename: Africa
authors.initials: A
authors.lastname: Vales
authors.affiliation: Imaging Unit and Cancer Imaging Laboratory, CIMA, Pamplona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Galarraga
authors.affiliation: Instituto de Investigación Sanitaria de Navarra (IdisNA), Pamplona, Spain Department of Morphology, CIMA, Pamplona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Guembe
authors.affiliation: Instituto de Investigación Sanitaria de Navarra (IdisNA), Pamplona, Spain Imaging Unit and Cancer Imaging Laboratory, CIMA, Pamplona, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Ortiz de Solorzano
authors.affiliation: Centre for Sexual Health and HIV Research, University College London, London, United Kingdom.
authors.forename: Indrajit
authors.initials: I
authors.lastname: Ghosh
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Mala K
authors.initials: MK
authors.lastname: Maini
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain Instituto de Investigación Sanitaria de Navarra (IdisNA), Pamplona, Spain University Clinic of Navarra, Pamplona, Spain CIBERehd, University of Navarra, Pamplona, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain Instituto de Investigación Sanitaria de Navarra (IdisNA), Pamplona, Spain ggasegui@unav.es.
authors.forename: Gloria
authors.initials: G
authors.lastname: González-Aseguinolaza
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D004337:Drug Carriers; D015316:Genetic Therapy; D006510:Hepatitis B Antibodies / Q000097:blood; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000821:virology*; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000235:genetics; D019409:Interleukin-15 / Q000008:administration & dosage* / Q000235:genetics; D008099:Liver / Q000821:virology; D008822:Mice, Transgenic; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D004337:Drug Carriers; D006510:Hepatitis B Antibodies; D016898:Interferon-alpha; D019409:Interleukin-15