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Principal Investigator: Alexander Ploss
Organization: PRINCETON UNIVERSITY
Fiscal Year: 2024
Award: $598,764
Funding agency: National Institute of Allergy and Infectious Diseases
Project summary
Coinfection with HBV and HIV-1 is common, and HIV coinfection can exacerbate progression of viral hepatitis and
accelerate liver disease progression. In fact, endstage liver diseases, including fiboris/cirrhosis and hepatocellular
carcinoma, have become the most common causes of death in people living with HIV (PWH) worldwide. HIV
infection cannot be cured currently but can be efficiently suppressed with highly active or combination anti-retroviral
therapy (HAART or cART). Currently available HBV drugs can suppress viral replication, but only a small subset of
patients are cured by these treatments. Although a prophylactic vaccine is available for HBV, it has no therapeutic
benefit. Consequently, new therapeutic approaches are urgently needed to combat chronic HBV infection,
particularly in the context of HIV coinfection. Here, we will capitalize on several technical and conceptual
breakthroughs from our lab to establish proof-of-concept for interfering with persistent HBV infection virologically.
We have recently made important discoveries that provide a strong foundation for the major direction of this
proposal. The Ploss lab identified key components of the DNA lagging strand synthesis machinery that are
necessary and sufficient for formation of HBV cccDNA, the replication intermediate crucial for viral persistence.
Clinical data from HBV patients indicate that cccDNA turnover occurs relatively rapidly (several months), offering a
possibility of curing HBV with finite therapy by completely blocking cccDNA replenishment. Thus, we aim to
determine whether liver-specific transient genetic disruption of polymerases and other co-factors in vivo can
abrogate HBV infection (Aim 1). Since we recently demonstrated that HBV cccDNA formation is supported in mouse
hepatocytes, we can take advantage of the power of mouse genetics to rigorously test our hypothesis that genetic
distruption of host factors involved in cccDNA formation can abrogate HBV infection. Furthermore, we will extend
our analysis to blocking HBV chronicity in the context of an underlying HIV coinfection (Aim 2). To achieve this
goal, we will take advantage of a novel humanized mouse model co-engrafted with HLA-matched human
hepatocytes and components of a human hematolymphoid system. Our preliminary data demonstrate that such
dually engrafted mice support chronic infections with both HBV and HIV and can mount antigen-specific T cell
responses. This humanized mouse model provides unprecedented opportunities for studying the complex interplay
of HBV/HIV co-infections and will be deployed here to test rigorously whether blocking HBV cccDNA formation can
abrogate HBV persistence.
We will capitalize on our extensive complementary expertises in virology and immunology of HIV-1/HBV (Su),
hepatitis viruses (Ploss) and humanized mouse technology to achieve these exciting aims. Our work will advance
the field of HBV and HIV-1 research by showing that a novel small animal model can be successfully used to
understand HIV/HBV coinfection and immune responses and to model treatments for the associated liver disease.
Terms: <AAV delivered><AAV delivery><AAV-based delivery><AAV-based viral delivery><AAV-mediated delivery><AIDS><AIDS Virus><Acceleration><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Adeno-associated-virus-based delivery><Affect><Animal Model><Animal Models and Related Studies><Anti-viral Therapy><Biochemical><Cause of Death><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Immune Function><Cellular Physiology><Cellular Process><Chronic><Chronic Hepatitis B><Circular DNA><Circulation><Cirrhosis><Clinical Data><Complex><DNA><DNA Damage Repair><DNA Repair><Data><Deoxyribonucleic Acid><Disease Progression><Double Stranded DNA Virus><Drugs><Engraftment><FOLT><Family><Folate Transporter><Foundations><Genetic><Goals><HAART><HBV><HBV infection><HIV><HIV Infections><HIV-1><HIV-I><HIV1><HTLV-III Infections><HTLV-III-LAV Infections><Hepadnaviridae><Hepadnavirus><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatitis B Infection><Hepatitis B Virus><Hepatitis Viruses><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatocyte><Hepatoma><Highly Active Antiretroviral Therapy><Homologous Serum Hepatitis Virus><Host Factor><Host Factor Protein><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Human immunodeficiency virus 1><IFC1><Immune response><Immune system><Immunity><Immunological response><Immunology><Impairment><In Vitro><Incidence><Individual><Inflammation><Integration Host Factors><Intestinal Folate Carrier 1><Knock-out><Knockout><LAV-HTLV-III><Lesion><Liver><Liver Cells><Liver Cells Carcinoma><Liver Fibrosis><Liver diseases><Lymphadenopathy-Associated Virus><Measures><Medication><Mice><Mice Mammals><Modeling><Modern Man><Monitor><Morbidity><Morbidity - disease rate><Murine><Mus><Pathogenesis><Patients><Persons><Pharmaceutical Preparations><Polymerase><Preventative vaccine><Preventive vaccine><Primary carcinoma of the liver cells><Prophylactic vaccine><Public Health><RFC1><Recombinants><Reduced Folate Carrier 1><Relaxation><Research><Risk><SLC19A1><SLC19A1 gene><Solute Carrier Family 19 (Folate Transporter), Member 1><Subcellular Process><System><T cell response><Technology><Testing><Therapeutic><Unscheduled DNA Synthesis><Viral><Viral Diseases><Viral Genome><Viral hepatitis><Viremia><Virus Diseases><Virus Replication><Virus-HIV><Work><adeno-associated viral vector delivery><adeno-associated virus delivery><adeno-associated virus mediated delivery><adenovirus mediated delivery><anti-hepatitis B><antigen-specific T cells><antiretroviral therapy><antiretroviral treatment><chronic HBV infection><chronic hepatitis B virus infection><chronic infection><cirrhotic><co-infection><cofactor><coinfection><combat><delivered with AAV><delivery with AAV><drug/agent><dsDNA Virus><end stage liver disease><end stage liver failure><fibrotic liver><hepatic body system><hepatic disease><hepatic fibrosis><hepatic organ system><hepatitis virus infection><hepatopathy><host response><humanized mice><humanized mouse><immune function><immune health><immune system health><immune system response><immunoresponse><improved><in vivo><infected with HBV><infected with hepatitis B><infected with hepatitis B virus><infection with HBV><infection with hepatitis B virus><insight><liver carcinoma><liver disorder><model of animal><mortality><mouse genetics><mouse model><murine model><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><persistent infection><repair><repaired><viraemia><viral infection><viral infectious disease treatment><viral multiplication><viral replication><viral sepsis><virology><virus genome><virus infection><virus multiplication><virus-induced disease><virusemia>