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Principal Investigator: ASHWIN BALAGOPAL
Organization: TRIAD NATIONAL SECURITY, LLC
Fiscal Year: 2024
Award: $904,941
Funding agency: National Institute of Allergy and Infectious Diseases
Summary
Significance: Hepatitis B virus (HBV) infects ~260 million people worldwide and is the leading cause of liver
disease and hepatocellular carcinoma (HCC) in the world. Despite an effective vaccine for infection prevention,
chronic hepatitis B virus infection (CHB) is difficult to cure once established. The viral genetic material enters
the infected cell's nucleus generating a stable covalently closed-circular DNA (cccDNA) molecule or a linear
form that integrates into the host cell's chromosome (iDNA). Existing treatments have little effect on cccDNA
and as a result have poor success rates. Treatment interruption often leads to rebound of HBV DNA and
recurrent hepatitis. In addition, even with treatment, liver disease in CHB often progresses to decompensated
cirrhosis requiring liver transplantation. This process is exacerbated by several viral co-infections, such as with
HIV or hepatitis C virus (HCV). Thus, improved therapeutics for CHB cure are required.
Innovation: Our proposal is innovative in three aspects. i) access to precious and unique samples of liver
tissue; ii) using state-of-the-art experimental techniques for single cell analyses and contemporaneous blood
biomarkers; iii) development of new multi-scale models of HBV infection informed by our rich data sets, which
are designed for clinical usefulness.
Approach: HBV has a complex lifecycle comprising intracellular and extracellular phases. Our team has
developed tools to interrogate the intracellular phase of HBV at the single-hepatocyte level. We have made
preliminary observations of HBV in single cells but have only recently begun to link the intracellular and
extracellular phases of HBV. Thus, we are poised to uncover key links in HBV biology between blood and liver.
Using an integrated approach, we propose developing models of HBV that characterize replication in the
organism uniting our understanding of intracellular and extracellular phases of the virus. Our specific aims are:
i) To develop integrated models of intracellular and extracellular HBV replication, measuring and
modeling a comprehensive set of HBV-related biomarkers in the blood and at the single-cell level in the liver, in
untreated and treated CHB; and ii) To develop models of HBV spatial spread and persistence in the liver,
using single-cell viral sequencing of HBV to make spatial linkages between genetically related HBV variants in
the liver. These data and models will allow inferences about local versus non-local HBV spread. Specifically,
we will test if clonal proliferation of HBV infected hepatocytes may contribute to continued persistence of
infected cells, which has important implications not only for cure research but also for HCC oncogenesis.
Impact: As multiple novel compounds for HBV treatment are in development, the timely insights generated in
this proposal will fill gaps in our understanding of HBV replication and pathogenesis. Previous efforts by us and
others in modeling HCV and HIV were important in the development of successful therapies for those
infections. We expect the new data and models generated here to have the same impact in advancing HBV
therapy.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Anti-viral Agents><Anti-viral Therapy><Antigens><Au antigen><Australia Antigen><Binding><Biological Markers><Biology><Blood><Blood Reticuloendothelial System><Body Tissues><Cell Body><Cell Nucleus><Cells><Chromosomes><Chronic><Chronic Hepatitis B><Circular DNA><Cirrhosis><Clinical><Clinical Markers><Collaborations><Complex><Data><Data Set><Development><Disease><Disorder><Distant><Equilibrium><Gene Transcription><Genetic Materials><Genetic Transcription><Genome><HBV><HBsAg><HBsAg (hepatitis B surface antigen)><HCV><HCV co-infection><HCV coinfection><HCV/HIV><HIV><HIV and HCV><HIV and hepatitis C><HIV-HCV><HIV/HCV><HIV/Hepatitis C><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatic Transplantation><Hepatitis><Hepatitis B><Hepatitis B Surface Antigens><Hepatitis B Virus><Hepatitis C co-infection><Hepatitis C virus><Hepatitis Viruses><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatocyte><Hepatoma><Homologous Serum Hepatitis Virus><Human><Human Immunodeficiency Viruses><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><Infection><Infection prevention><Interruption><Island><Knowledge><LAV-HTLV-III><Life Cycle><Life Cycle Stages><Link><Liver><Liver Cells><Liver Cells Carcinoma><Liver Grafting><Liver Transplant><Liver diseases><Liver lesion biopsy><Lymphadenopathy-Associated Virus><Math Models><Measurement><Measures><Medicine><Modeling><Modern Man><Molecular Interaction><NIH><National Institutes of Health><Non-Polyadenylated RNA><Nucleic Acids><Nucleus><Oncogenesis><Organ><Organism><Paper><Pathology><Persons><Phase><Phylogenetic Analysis><Phylogenetics><Prevent infection><Primary carcinoma of the liver cells><Process><Production><Proliferating><Proteins><Publishing><RNA><RNA Expression><RNA Gene Products><Recurrence><Recurrent><Research><Residual><Residual state><Ribonucleic Acid><Sampling><Single cell seq><Stream><Techniques><Testing><Therapeutic><Tissues><Transcription><Translational Research><Translational Science><Trees><United States National Institutes of Health><Vaccines><Variant><Variation><Viral><Viral Diseases><Viral Genetics><Viral Genome><Viral Hepatitis B><Viral Pathogenesis><Virion><Virus><Virus Diseases><Virus Particle><Virus Replication><Virus-HIV><Whole Organism><aPD-1><aPD1><anti programmed cell death 1><anti-PD-1><anti-PD1><anti-programmed cell death protein 1><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antiPD-1><antiPD1><balance><balance function><bio-markers><biologic marker><biomarker><chronic HBV infection><chronic hepatitis B virus infection><cirrhotic><clinical relevance><clinically relevant><co-infection><coinfection><depository><design><designing><developmental><disease model><disorder model><end stage liver disease><end stage liver failure><extracellular><hepatic body system><hepatic disease><hepatic organ system><hepatitis C coinfection><hepatitis C virus co-infection><hepatitis C virus coinfection><hepatitis associated antigen><hepatopathy><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><improved><innovate><innovation><innovative><insight><intrahepatic><life course><liver biopsy><liver carcinoma><liver disorder><liver transplantation><living system><mathematic model><mathematical model><mathematical modeling><multi-scale computational modeling><multi-scale mathematical modeling><multi-scale modeling><multiscale computational modeling><multiscale mathematical modeling><multiscale modeling><novel><repository><serum hepatitis><single cell analysis><single cell next generation sequencing><single cell sequencing><success><tool><translation research><translational investigation><tumorigenesis><viral DNA><viral RNA><viral infection><viral infectious disease treatment><viral multiplication><viral replication><virus DNA><virus RNA><virus genetics><virus genome><virus infection><virus multiplication><virus pathogenesis><virus-induced disease><αPD-1><αPD1>