Wednesday, May 8, 2024
5/8/2024
Abstract Hepatitis B virus (HBV) is one of the most important human pathogens. Globally, there are approximately 300 million people that are chronically infected by this virus, resulting in nearly 1 million deaths every year. The current treatments for chronic HBV patients rely mostly on nucleos/tide analogs (NAs), which include entecavir, tenofovir and telbivudine. These NAs, which target the viral reverse transcriptase, have little effect on the viral genome in the nucleus of infected hepatocytes and do not suppress viral gene expression. As such, they fail to generate sustained response in the vast majority of HBV patients. We have recently discovered that the cytokine interleukin-1ß (IL-1ß) can effectively suppress HBV gene expression by downregulating the expression of PPARa and FOXO3, which are two transcription factors critical for HBV gene expression. The ability of IL-1ß to shut down HBV gene expression raises the possibility that IL-1ß may be used as a novel therapeutic agent to treat HBV patients, as the loss of HBV gene expression and the consequent loss of circulating HBV surface antigen (HBsAg) may result in the appearance of antibodies directed against HBsAg to result in “functional cure” and may even lead to the activation of CD8+ T cells to result in the removal of HBV-infected hepatocytes. In this application, we will explore these possibilities. In addition, our preliminary data indicated that repaglinide, an FDA-approved diabetes drug that was found to inhibit the binding of FOXO3 to its target DNA sequence, could suppress HBV gene expression. For that reason, we will also test whether rapaglinide can be repurposed to treat HBV patients. During the R21 phase of this application, we will use PXB cells, which are human hepatocytes isolated from humanized PXB mice, for HBV infection studies. We will also use HBV transgenic mice to test the aniviral effects of IL-1ß and rapaglinide. During the R33 phase, we will use a mouse model with persistent HBV replication that we recently developed to study the antiviral effects of IL-1ß and repaglinide and host immune responses. If it is necessary, we will also generate repaglinide derivatives to improve its efficacy against HBV. In addition, we will use humanized FRG mice to test the anti-HBV effects of IL-1ß, repaglinide and their combined use with entecavir. The success of our proposed studies will lead to novel therapeutics for the treatment of HBV patients.
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