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Mechanisms of Hepadnavirus Assembly and Replication

Award Number: R37AI043453
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: 02/15/1999
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Mechanisms of Hepadnavirus Assembly and Replication - Hepatitis B virus (HBV) is a major cause of chronic viral hepatitis that increases dramatically the risk of liver cancer and other end-stage liver diseases such as cirrhosis. The major obstacle to curing chronic HBV infection is the persistence of the viral nuclear episome, the covalently closed circular (CCC) DNA, which is derived from the relaxed circular (RC) DNA contained within the viral nucleocapsid. Moreover, the inability of mouse hepatocytes to support CCC DNA formation remains a major hurdle in the development of an immuno-competent mouse model for HBV infection. This MERIT Award Extension application builds on, and extends, our current work on the disassembly of viral nucleocapsids (uncoating), which releases the RC DNA into the host cell nucleus, a prerequisite step for nuclear CCC DNA formation but also exposing RC DNA for potential degradation or triggering of host cell DNA sensing and immune responses. The main goal of the Extension is to better understand viral and host control of HBV CCC DNA formation and infection. Four Specific Aims are proposed. Aim 1 will elucidate the deficiencies in mouse hepatocytes for HBV infection. Aim 2 will develop cell-free systems for nucleocapsid uncoating and CCC DNA formation. Aim 3 will define the late HBV entry events controlled by the viral capsid and host factors. Aim 4 will assess the role of DNA sensing in HBV infection. RELEVANCE (See instructions): The hepatitis B virus (HBV) is a global cause of chronic liver diseases, including liver cirrhosis and cancer. We propose to elucidate the mechanisms of, and viral and host factors involved in, the viral trafficking events during infection and the disassembly of HBV nucleocapsid, which are essential but poorly understood steps in viral replication and contribute to the host tropism of HBV. These studies will bring novel insights into HBV infection and nucleocapsid disassembly and facilitate ongoing efforts to develop novel antiviral agents targeted at these processes as well as mouse models of 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: 2025 ( Subtotal = $472,793 )
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	000	28	8/15/2025	NON-COMPETING CONTINUATION	$472,793
														Subtotal = $472,793

Issue Date FY: 2024 ( Subtotal = $483,339 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	002	27	8/12/2024	NON-COMPETING CONTINUATION	$483,339
2024	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	001	26	7/25/2024	EXTENSION WITH OR WITHOUT FUNDS	$33,468
2024	2022	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	000	25	7/25/2024	NON-COMPETING CONTINUATION	-$33,468
														Subtotal = $483,339

Issue Date FY: 2023 ( Subtotal = $494,893 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	000	26	6/16/2023	EXTENSION WITH OR WITHOUT FUNDS	$494,893
														Subtotal = $494,893

Issue Date FY: 2022 ( Subtotal = $380,601 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	000	25	8/11/2022	NON-COMPETING CONTINUATION	$380,601
														Subtotal = $380,601

Issue Date FY: 2021 ( Subtotal = $380,704 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	000	24	8/5/2021	NON-COMPETING CONTINUATION	$380,704
														Subtotal = $380,704

Issue Date FY: 2020 ( Subtotal = $380,803 )
2020	2020	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	000	23	8/11/2020	NON-COMPETING CONTINUATION	$380,803
														Subtotal = $380,803

Issue Date FY: 2019 ( Subtotal = $702,585 )
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	002	22	8/21/2019	NON-COMPETING CONTINUATION	$373,044
2019	2018	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	001	21	7/29/2019	COMPETING CONTINUATION	$0
2019	2018	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	000	21	4/23/2019	COMPETING CONTINUATION	$329,541
														Subtotal = $702,585

Grand Total All Awards = $3,295,718

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Mechanisms of Hepadnavirus Assembly and Replication

Award Number: R37AI043453

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: 02/15/1999

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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