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Complementary Effects of Interleukin-15 and Alpha Interferon Induce Immunity in Hepatitis B Virus Transgenic Mice

التفاصيل البيبلوغرافية
العنوان: Complementary Effects of Interleukin-15 and Alpha Interferon Induce Immunity in Hepatitis B Virus Transgenic Mice
المؤلفون: Gloria González-Aseguinolaza, Miguel Galarraga, Itziar Otano, Cristina Olagüe, Lucia Vanrell, Laura Guembe, Africa Vales, Mirja Hommel, Irene Gil-Farina, Marianna Di Scala, Jesús Prieto, Carlos Ortiz de Solorzano, Indrajit Ghosh, Mala K. Maini
المصدر: Journal of Virology
بيانات النشر: American Society for Microbiology, 2016.
سنة النشر: 2016
مصطلحات موضوعية: 0301 basic medicine, Hepatitis B virus, T cell, Immunology, Alpha interferon, Mice, Transgenic, CD8-Positive T-Lymphocytes, Biology, medicine.disease_cause, Microbiology, Virus, Adenoviridae, Gene Delivery, 03 medical and health sciences, Hepatitis B, Chronic, 0302 clinical medicine, Immune system, Virology, medicine, Animals, Hepatitis B Antibodies, Interleukin-15, Drug Carriers, Interferon-alpha, Genetic Therapy, Viral Load, Hepatitis B, medicine.disease, 3. Good health, Disease Models, Animal, Treatment Outcome, 030104 developmental biology, medicine.anatomical_structure, Liver, Insect Science, Viral load, CD8, 030215 immunology
الوصف: 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. IMPORTANCE 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.
تدمد: 1098-5514
0022-538X
DOI: 10.1128/jvi.01030-16
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2e58b4254748468ad90c3f60e0b9a992
https://doi.org/10.1128/jvi.01030-16
Rights: OPEN
رقم الانضمام: edsair.doi.dedup.....2e58b4254748468ad90c3f60e0b9a992
قاعدة البيانات: OpenAIRE
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