Product(s) used in this publication: PepMix™ Peptide Pools
In chronic hepatitis B (CHB) failure of HBV control is associated with T cell dysfunction. HBVtransgenicmice mirror many features of the human disease, including T-cell unresponsiveness, and thus represent an appropriate model to test novel therapeutic strategies. To date the tolerant state of CD8+ T cells in these animals could only be altered by strong immunogens or immunization with HBV antigen-pulsed dendritic cells, however, the induced effectors were unable to suppress viral gene expression or replication. Because of their known stimulatory properties, this study explored the therapeutic potential of a liver-directed gene transfer of IFN-α and IL-15 in a murine model of CHB using AAV delivery. Their combination resulted not only in a reduction of the viral load in the liver and the induction of an antibody response but gave rise to functional and specific CD8+ immunity. Furthermore, when transferring splenic and intrahepatic lymphocytes from IFN-α/IL-15-treated animals to new HBV carriers, partial antiviral immunity was achieved. Contrary to previous observations made using either cytokine alone, a markedly attenuated PD-L1 induction in hepatic tissue was observed upon co-administration. An initial study with CHB patient samples also gave promising results. Hence, synergizing the effects of two stimulating cytokines, IL-15 and IFN-α, demonstrated a potent approach to significantly enhance the CD8+ T cell response in a state of immune hyporesponsiveness and 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, 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.
Copyright © 2016 Di Scala et al.