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Human mechanisms of virus persistence in an AAV-based mouse model of chronic HBV infection

Award Number: R01AI148354
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/06/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Human mechanisms of virus persistence in an AAV-based mouse model of chronic HBV infection - PROJECT SUMMARY Chronic hepatitis B virus (HBV) infection is associated with an ineffective T cell response that fails to control the virus. While the precise mechanism of T cell dysfunction in chronic hepatitis B is not well understood, prior studies using blood and liver tissue from acute and chronic HBV patients have identified a number of critical immunological mechanisms that may contribute to this poor immune response. These mechanisms include the killing of HBV-specific T cells by liver-resident natural killer (NK) cells, a general tolerogenic environment in the liver that is manifested by immunosuppressive immune cells, cytokines, and metabolic pathways, and the loss of T cell function through inhibitory receptor signaling pathways and exhaustion. The study of HBV-host interactions and the development of new curative immunotherapies for chronic hepatitis B have been hampered by the lack of physiological animal models for chronic infection. A new mouse model of HBV replication was recently described that is based on adeno-associated virus (AAV)-mediated transduction of the liver with the HBV genome, which leads to persistent virus replication and immune tolerance to HBV antigens. Compared to other mouse models of HBV replication, the AAV-HBV model has important advantages, including physiological intrahepatic immune priming, technical ease and reproducibility, peripheral T and B cell tolerance to HBV, and the ability to study virus elimination from the liver. Using this model, we will test the hypothesis that HBV therapeutic vaccine efficacy can be enhanced by manipulating mechanisms of immune dysfunction to promote viral clearance. Our general approach will be to combine AAV-HBV transduction with genetically modified mice and antibody-mediated depletion/blockade to evaluate the importance of immune cells, cytokines, and regulatory pathways for eliciting functional CD8+ T cell responses and controlling HBV following therapeutic immunization. To evaluate our hypothesis, we will carry out three specific aims. First, we will assess the inhibition of HBV- specific T cells by NK cells. Second, we will define the role of regulatory cells, cytokines, and metabolic pathways. Third, we will evaluate T cell inhibitory receptor function and exhaustion. The knowledge that will be gained from this research will impact the field in two important ways. First, it will provide new mechanistic insight into the relationship between T cell dysfunction and HBV persistence, and form a strong foundation for future studies using the AAV-HBV model to better understand the virus-host interactions that are observed in humans. Second, it will reveal new immunotherapeutic targets for potential approaches to cure 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: 2024 ( Subtotal = $491,566 )
2024	2024	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE # A34	ALBANY	NY	12208	ALBANY	USA	Allergy and Infectious Diseases Research	000	5	4/12/2024	NON-COMPETING CONTINUATION	$491,566
														Subtotal = $491,566

Issue Date FY: 2023 ( Subtotal = $491,566 )
2023	2023	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Allergy and Infectious Diseases Research	000	4	4/12/2023	NON-COMPETING CONTINUATION	$491,566
														Subtotal = $491,566

Issue Date FY: 2022 ( Subtotal = $491,566 )
2022	2022	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Allergy and Infectious Diseases Research	000	3	4/27/2022	NON-COMPETING CONTINUATION	$491,566
														Subtotal = $491,566

Issue Date FY: 2021 ( Subtotal = $491,566 )
2021	2021	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Allergy and Infectious Diseases Research	000	2	4/12/2021	NON-COMPETING CONTINUATION	$491,566
														Subtotal = $491,566

Issue Date FY: 2020 ( Subtotal = $490,561 )
2020	2020	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Allergy and Infectious Diseases Research	000	1	5/5/2020	NEW	$490,561
														Subtotal = $490,561

Grand Total All Awards = $2,456,825

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Human mechanisms of virus persistence in an AAV-based mouse model of chronic HBV infection

Award Number: R01AI148354

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/06/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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