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Principal Investigator: Eleftherios Michailidis
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $74,814
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
There are approximately a quarter of a billion people worldwide chronically infected with hepatitis B virus (HBV)
who are at risk of developing liver cirrhosis and hepatocellular carcinoma. The loss of life due to HBV-related
complications each year is about 820,000 people. At the same time human immunodeficiency virus (HIV) infects
about 38 million people worldwide. Among those, 7.4% globally and 15-28% in highly endemic areas are also
infected with HBV. HIV co-infections pose a serious health burden as they accelerate the progression to liver
cirrhosis and liver cancer with mechanisms that are still not well understood.
Chronicity of HBV infections is linked to the stability and maintenance of the covalently closed circular DNA
(cccDNA), which is the nuclear form of the HBV genome. As HBV infects human hepatocytes in the liver, the
cccDNA is established in these cells and strategies that aim to inactivate or eliminate it are considered the
solution to a functional cure. Current treatments against chronic HBV include nucleoside analogs and interferon
α. While nucleoside analogs do not directly affect the cccDNA, a limited number of patients that receive interferon
α or nucleoside analogs can resolve the infection and achieve a cure. The need for a global HBV cure is urgent,
which is also why several approaches and investigational compounds aim for a cure.
HBV is an exclusive hepatotropic virus that only infects human hepatocytes. HBV studies have been hindered
by limited cell culture systems that include hepatoma cells after overexpression of the HBV receptor NTCP and
primary human hepatocytes. The latter are the most physiologically relevant cells, but their availability and the
inherent limitations of primary cells makes it difficult to use them to recapitulate the complete HBV lifecycle. To
this end, we have developed cell culture systems based on primary human hepatocytes, isolated from
humanized mice, that efficiently support long-term HBV infection and spread. Moreover, we developed a system
of isolating these cells from HBV-infected humanized mice which provides unique opportunities for research.
Specifically, cells are chronically infected with HBV and therefore carry high levels of cccDNA, which allows for
modeling chronic HBV in vitro. Here we propose to use these innovative hepatocyte systems to establish robust
co-cultures with CD4+ T cells for studying HIV/HBV co-infections in physiologically relevant primary cell culture
systems. Overall, with our proposed work we will gain insights on the effects of HIV co-infection on HBV lifecycle
and hepatocyte responses and we will establish a platform to identify novel antiviral strategies with the goal for
a functional HBV cure.
Terms: <(IFN) α><(IFN)-α><(IFN)α><3-D><3-Dimensional><3D><AIDS Virus><Acceleration><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affect><Alferon><Antigens><Area><Au antigen><Australia Antigen><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cell Body><Cell Culture System><Cell Isolation><Cell Line><Cell Segregation><Cell Separation><Cell Separation Technology><CellLine><Cells><Chronic><Chronic Hepatitis B><Circular DNA><Co-culture><Cocultivation><Coculture><Coculture Techniques><Culturing, in vitro Vertebrate, Primary><Detection><EC 2.7.7.49><Exhibits><Gene Transcription><Genetic Transcription><Goals><HBV><HBV Vaccine><HBV infection><HBsAg><HBsAg (hepatitis B surface antigen)><HIV><HIV Infections><HTLV-III Infections><HTLV-III-LAV Infections><Health><Hepatic Cancer><Hepatic Cells><Hepatic Cirrhosis><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatitis B Infection><Hepatitis B Surface Antigens><Hepatitis B Vaccines><Hepatitis B Virus><Hepatitis B virus vaccine><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatocyte><Hepatoma><Homologous Serum Hepatitis Virus><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><IFN Alpha><IFN α><IFN-α><IFNa><IFNα><Immune response><Immunological response><In Vitro><Individual><Infection><Interferon Alfa-n3><Interferon alpha><Interferon-α><Investigation><Knowledge><LAV-HTLV-III><Leukocyte Interferon><Life><Life Cycle><Life Cycle Stages><Link><Liver><Liver Cells><Liver Cells Carcinoma><Liver Cirrhosis><Liver diseases><Lymphadenopathy-Associated Virus><Lymphoblast Interferon><Lymphoblastoid Interferon><Maintenance><Malignant neoplasm of liver><Measurement><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Nature><Non-Polyadenylated RNA><Nuclear><Patients><Persons><Physiologic><Physiological><Primary Cell Cultures><Primary carcinoma of the liver cells><RNA><RNA Expression><RNA Gene Products><RNA Seq><RNA Transcriptase><RNA sequencing><RNA-Dependent DNA Polymerase><RNA-Directed DNA Polymerase><RNAseq><Research><Reverse Transcriptase><Revertase><Ribonucleic Acid><Risk><Strains Cell Lines><System><T4 Cells><T4 Lymphocytes><Time><Transcription><Viral><Viral Diseases><Viral Genome><Viral Receptor><Virus><Virus Diseases><Virus Receptors><Virus Replication><Virus-HIV><Withholding Treatment><Work><antiretroviral therapy><antiretroviral treatment><biomarker identification><cell sorting><cessation of treatment><chronic HBV infection><chronic hepatitis B virus infection><chronic infection><co-infection><coinfection><cultured cell line><curative intervention><curative therapeutic><curative therapy><curative treatments><develop drug resistance><drug development><drug resistance development><e Antigens><global gene expression><global transcription profile><hepatic body system><hepatic disease><hepatic organ system><hepatitis associated antigen><hepatoma cell><hepatopathy><high risk><host response><humanized mice><humanized mouse><identification of biomarkers><identification of new biomarkers><immune system response><immunogen><immunoresponse><infected with HBV><infected with hepatitis B><infected with hepatitis B virus><infection with HBV><infection with hepatitis B virus><innovate><innovation><innovative><insight><life course><liver cancer><liver carcinoma><liver disorder><liver malignancy><mRNA><malignant liver tumor><marker identification><novel><nucleoside analog><overexpress><overexpression><persistent infection><predictive biomarkers><predictive marker><predictive molecular biomarker><prophylactic><response><spheroids><three dimensional><transcriptome><transcriptome sequencing><transcriptomic sequencing><transcriptomics><treatment cessation><vaccine against hepatitis B><viral infection><viral multiplication><viral rebound><viral replication><virus core><virus genome><virus infection><virus multiplication><virus rebound><virus-induced disease>