Project Grant R01AI183855

NOVEL MOUSE MODELS OF HEPATITIS B VIRUS INFECTION AND REPLICATION - SUMMARY HEPATITIS B VIRUS (HBV) IS A COMMON CAUSE OF LIVER DISEASES SUCH AS ACUTE AND CHRONIC HEPATITIS, LIVER FIBROSIS, CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA (HCC). HBV INFECTION CONTINUES TO POSE A MAJOR THREAT TO GLOBAL PUBLIC HEALTH, AFFECTING MORE THAN 250 MILLION PEOPLE WORLDWIDE. ALTHOUGH LICENSED VACCINES CAN EFFECTIVELY PREVENT NEW HBV INFECTION, THEY DO NOT OFFER THERAPEUTIC BENEFITS TO THE HUNDREDS OF MILLION PEOPLE ALREADY INFECTED WITH HBV. THE BIGGEST CHALLENGE TO CURE CHRONIC HEPATITIS B IS THE LACK OF THERAPEUTICS TO ELIMINATE HBV COVALENTLY CLOSED CIRCULAR DNA (CCCDNA), WHICH IS RESPONSIBLE FOR HBV PERSISTENCE. CURRENT STANDARD ANTIVIRAL THERAPIES CONSISTING OF INTERFERON AND/OR NUCLEOSIDE ANALOGS CAN SUPPRESS HBV REPLICATION BUT DO NOT SIGNIFICANTLY AFFECT THE LEVEL OF HBV CCCDNA. THUS, THERE IS AN URGENT NEED TO DISCOVER AND DEVELOP NEW CLASSES OF ANTIVIRAL DRUGS CAPABLE OF ELIMINATING HBV INFECTION. OVER THE YEARS, THE SEARCH FOR A CURE OF CHRONIC HEPATITIS B HAS BEEN HAMPERED BY THE LACK OF ROBUST CELL CULTURE SYSTEMS OF HBV PROPAGATION AND SMALL ANIMAL MODELS OF HBV INFECTION AND REPLICATION. THE DISCOVERY OF SODIUM TAUROCHOLATE COTRANSPORTING POLYPEPTIDE (NTCP) AS AN HBV RECEPTOR HAS MADE IT POSSIBLE TO DEVELOP CELL CULTURE MODELS OF HBV INFECTION. HOWEVER, NTCP PER SE DOES NOT CONFER HBV SUSCEPTIBILITY IN TRANSGENIC MICE, SUGGESTING OTHER CO-RECEPTORS THAT MAY BE NEEDED FOR MORE EFFICIENT HBV INFECTION IN VIVO. THROUGH PRELIMINARY STUDIES, WE HAVE FOUND THAT HUMAN APOLIPOPROTEIN E (APOE) AND APOE-BINDING RECEPTORS SUCH AS HEPARAN SULFATE PROTEOGLYCANS (HSPGS) AND THE LOW-DENSITY LIPOPROTEIN RECEPTOR (LDLR) FAMILY PROTEINS PROMOTE HBV INFECTION. MORE SIGNIFICANTLY, OUR PRELIMINARY DATA SUGGEST THAT CO-EXPRESSION OF NTCP WITH HUMAN APOE AND LDLR IN THE PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9)-DEFICIENT MICE COULD CONFER HBV SUSCEPTIBILITY. STRIKINGLY, INOCULATION OF NTCP/APOE3/LDLR/PCSK9-/- MICE WITH HBV DERIVED FROM HBV-TRANSGENIC MICE EXPRESSING HUMAN APOE3 RESULTED IN A HIGH HBV VIREMIA (~106 GENOME COPY EQUIVALENTS/ML) IN THE MOUSE SERA AFTER ONE WEEK OF HBV INOCULATION. WE HYPOTHESIZE THAT THE CELL TROPISM OF HBV IS NOT ONLY DETERMINED BY ITS RECEPTOR NTCP BUT ALSO BY HOST FACTORS PROMOTING HBV INFECTION, TRANSCRIPTION, AND REPLICATION. THE OVERALL GOAL OF THIS APPLICATION IS TO DEVELOP ROBUST MOUSE MODELS OF HBV INFECTION AND REPLICATION FOR INVESTIGATION OF HBV INFECTION, TRANSCRIPTION, REPLICATION, PATHOGENESIS, AND HOST IMMUNE RESPONSE TO HBV INFECTION AS WELL AS FOR EVALUATION OF HBV-SPECIFIC ANTIVIRAL DRUGS AND THERAPEUTIC STRATEGIES IN VIVO. OUR SPECIFIC AIMS ARE: 1) TO DEVELOP AN IMMUNOCOMPETENT MOUSE MODEL OF HBV INFECTION AND REPLICATION; 2) TO CONSTRUCT NOVEL MOUSE MODELS OF HBV PERSISTENCE; AND 3) TO DEVELOP AN IMMUNODEFICIENT MOUSE MODEL OF HBV INFECTION AND TO DETERMINE HOST IMMUNE CONTROL OF HBV INFECTION. THE SUCCESSFUL COMPLETION OF THIS APPLICATION WILL HAVE A PROFOUND IMPACT ON HBV RESEARCH BY PROVIDING NOVEL MOUSE MODELS OF HBV INFECTION AND REPLICATION AND NEW THERAPEUTIC STRATEGIES TOWARDS THE ULTIMATE CURE OF CHRONIC HEPATITIS B.