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Worldwide, 350 million people suffer from chronic hepatitis B virus (HBV) infection and approximately 600,000 people die annually because of HBV-induced liver cirrhosis and hepatocellular carcinoma. Available treatment options include nucleoside/nucleotide analogues (NAs) that are highly effective in suppressing hepatitis B virus (HBV) replication and preventing liver disease progression. However, NAs do not affect HBV RNA transcription from the covalently-closed circular DNA molecule of HBV within infected hepatocytes and, therefore, have only limited impact on HBV surface antigen serum levels. Since NAs do not directly stimulate immune clearance of HBV-infected hepatocytes, in most cases viral replication rebounds upon cessation of therapy. As a consequence, prolonged or even life-long treatment of HBV is needed. This long-lasting therapy is associated with high costs and the risk of emergence of drug resistant HBV variants. Pegylated interferon alpha (IFNα) is an alternative therapy for CHB. This cytokine is endowed with immunostimulatory properties and targets both HBV transcription and replication. Antiviral response to pegylated interferon alpha treatment is often durable but the use of this drug is limited due to low response rates and frequent side effects that are sometimes severe. Therefore, new and alternative treatment approaches for the control of CHB are warranted.
Animal models are essential to elucidate the molecular mechanisms implicated in the pathogenesis of a disease and for the development of new therapeutic approaches. One of the best surrogate models for the study of chronic hepatitis is the woodchuck model. Woodchucks are infected by the woodchuck Hepatitis virus (WHV) which belongs to the HBV family and provokes a pathology very similar to the one associated with HBV infection. However, this animal model is costly, difficult to handled, and limited in terms of availability and experimental tools. One of the main aims of this project was the development of murine models for chronic HBV and WHV infection. Mice are not naturally infected by those viruses because they lack a functional receptor, so we disease to use a subtle vector to introduce the vector genome of HBV and WHV in hepatocytes. We choose as subtle vector recombinant adeno-associated vector serotype 8 (AAV8) that infect murine liver with high efficacy. With this strategy we have been able to establish a model of chronic HBV infection, however, using a similar strategy we failed to develop a model for WHV. Thus we have continued with the characterization of HBV animal model, using it to test new therapeutic strategy. The second aim of this project, was the development of new therapeutic strategies for the treatment of chronic HBV infections that could be potentially apply to additional pathologies.
As indicate current treatment for chronic HBV infection consist on the administration for long periods of time of IFN-alpha. To improve this treatment we have generated AAV vectors expressing different inducers of the IFN type I pathway in the liver, to concentrate the cytokine to the target organ and to reduce systemic side effects. We have shown that these inducers can interfere with the replication of different viruses, including HBV, and even in models where the IFN response is blocked. In addition, we have generated AAV vectors carrying a transgen expression system which respond to unfolded protein response signalling pathway. We have tested this system carrying as therapeutic gene IFN-alpha showing its functionality in a mouse model. This induction bypasses the antagonistic ability of the virus to block IFN production. We finally have found a mechanism induced during virus infection that stimulates the expression of alternative spliced forms of STING. STING one of the intracellular sensors of pathogens and its activation result in the activation of an antiviral response by the cell. We have found, that these alternative forms can inhibit normal STING function, inducing a self-limiting antiviral response mechanism. These studies identify a potential new target to fight HBV chronic infection.
In summary, we have developed new animal models for the study of chronic HBV infection , furthermore have generated new experimental tools and identify new targets to fight chronic HBV infection and potentially other pathologies.