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Targeting hepatitis B virus cccDNA during HBV/HIV co-infection

Award Number: R01AI181664
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: 08/20/2024
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Targeting hepatitis B virus cccDNA during HBV/HIV co-infection - 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.


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 = $0 )
2026	2024	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	1	2/19/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $2,395,056 )
2025	2025	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	001	2	8/25/2025	EXTENSION WITH OR WITHOUT FUNDS	$2,395,056
2025	2024	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	1	8/25/2025	NEW	$0
														Subtotal = $2,395,056

Issue Date FY: 2024 ( Subtotal = $598,764 )
2024	2024	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	1	8/20/2024	NEW	$598,764
														Subtotal = $598,764

Grand Total All Awards = $2,993,820

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Targeting hepatitis B virus cccDNA during HBV/HIV co-infection

Award Number: R01AI181664

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: 08/20/2024

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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