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Mechanisms of HBx Recognition and Epigenetic Regulation of HBV cccDNA

Award Number: F31AI197467
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/30/2026
PERIOD OF PERFORMANCE END DATE: 03/29/2029

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Mechanisms of HBx Recognition and Epigenetic Regulation of HBV cccDNA - PROJECT SUMMARY/ABSTRACT Chronic Hepatitis B Virus (HBV) infection affects nearly 300 million individuals and is a leading cause of hepatocellular carcinoma worldwide. HBV persistence relies on the establishment of 1) the viral covalently closed circular DNA (cccDNA) minichromosome which serves as that viral transcriptional template and 2) the expression of the regulatory protein HBx which prevents cccDNA silencing. Due to limited in vitro and animal models that recapitulate transient events like cccDNA formation early during infection, the mechanisms through which HBx recognizes and regulates cccDNA remain poorly understood. The David lab strives to better understand the molecular mechanisms of chromatin regulation in disease. Towards this end, we have pioneered novel platforms to study HBV biology with the first methods to reconstitutes scarless cccDNA with infectious capacity and full- length HBx protein for biochemical and biophysical studies. We discovered that HBx directly binds to chromatin to induce decompaction in vitro and found that cccDNA histone occupancy is required for HBx expression early during infection. My proposal extends these findings by seeking to elucidate host epigenetic regulation of HBV transcription (Aim 1) and HBx-mediated cccDNA recognition (Aim 2). My working hypothesis is that HBx directly recognizes and decompacts the viral minichromosome to allow host epigenetic machinery to distinctly control viral transcription. We have shown that host histone incorporation onto cccDNA is important for HBV transcription. Importantly, we found that pharmacological disruption of viral chromatin assembly leads to reductions in HBV transcription, antigen secretion, and viral replication in hepatocyte models of infection. The proposed Aim 1 will identify host histone variants and chromatin remodelers that influence HBV transcriptional control. First, I will probe for the presence of active transcription- associated histone variants deposited onto cccDNA during infection using chromatin immunoprecipitation. I will then determine the effect on viral chromatin assembly and transcription of the loss of host epigenetic regulators implicated in cccDNA chromatin regulation using a limited shRNA screen and auxin-inducible degron tagging. In Aim 2, I will use biophysical approaches, such as biolayer interferometry, to define the determinants of HBx- nucleosome binding. I will then investigate changes in viral chromatin compaction due to this interaction through Mg2+ precipitation and MNase protection assays. If validated in vitro, I will expand to testing this phenomenon in cellulo using dCas9 to fluorescently label cccDNA and ATAC-see to measure and visualize host- and cccDNA- specific changes in chromatin accessibility in the absence and presence of HBx. Overall, Aim 2 will reveal new insights into HBx’s role in viral chromatin regulation. Successful completion of this project will reveal mechanisms for how HBx modulates HBV chromatin and uncover novel therapeutic targets for silencing or eradicating cccDNA, improving epigenetic strategies to develop a functional cure for chronic HBV infection.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $50,114 )
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	3/30/2026	NEW	$49,538
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Allergy and Infectious Diseases Research	002	1	4/13/2026	NEW	$0
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Allergy and Infectious Diseases Research	001	1	4/13/2026	NEW	$576
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Mechanisms of HBx Recognition and Epigenetic Regulation of HBV cccDNA

Award Number: F31AI197467

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/30/2026

PERIOD OF PERFORMANCE END DATE: 03/29/2029

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