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Hepatic Priming of CD4+ T cells Directs Effective Hepatitis B Virus Immunity

Award Number: F31DK135386
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/15/2024
PERIOD OF PERFORMANCE END DATE: 03/14/2027

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Hepatic Priming of CD4+ T cells Directs Effective Hepatitis B Virus Immunity - PROJECT SUMMARY/ABSTRACT Chronic infection with hepatitis B virus (HBV) is a leading global cause of end-stage liver disease and hepatocellular carcinoma; fatal outcomes that can be prevented when serum hepatitis B surface antigen (HBsAg) clearance is achieved, which rarely occurs with available treatments. HBsAg seroclearance is therefore the primary goal for next generation therapies. Whereas most adults who develop acute hepatitis B will clear HBsAg and produce HBsAg-specific antibodies (HBsAb), most young children and neonates fail to clear HBsAg and develop life-long infection. Most adults with chronic hepatitis B (CHB) therefore acquired infection in early life when the antiviral immune response proved ineffective. Understanding the immunologic differences responsible for the age gradient in HBsAg seroclearance provides a roadmap for identifying therapeutic targets for redirecting the HBV immune response towards HBsAg seroclearance. To achieve this objective, I will utilize both a well-established mouse model that recapitulates age-related serological outcomes observed in human HBV infections as well as already collected cytometry and single cell RNA sequencing (scRNAseq) data from an antiviral therapy withdrawal clinical trial. By employing these complementary sources of biological information in direct mouse-human comparison, I have the unique opportunity to make clinically relevant interrogations into the mechanisms of hepatic antigen presentation and the activation of CD4+ T cells by hepatic conventional dendritic cell (cDCs) that leads to HBsAg seroclearance. These studies will also identify and test potential therapeutic targets that alter the hepatic immune priming environment to augment the rate of HBsAg seroclearance in our mouse model. My proposal is composed of three specific aims. In Specific Aim 1 I will investigate the role of several co- stimulatory signaling pathways to an age-dependent capacity of hepatic cDCs to activate CD4+ T cells in vitro. Also, I will use scRNAseq data to identify transcriptomic differences in antigen presenting cell populations that are associated with HBsAg seroclearance in both mice and humans. In Specific Aim 2 I will use immunohistochemistry to image age-dependent immune cell interactions in hepatic tissues of mice and test whether these differences are indicative of age-dependent differences in T cell trafficking and organization in the liver parenchyma. Also, I will study CD4+ T cells from both mice and humans responding to HBV to again identify shared transcriptomic differences associated with HBsAg seroclearance. Finally, in Specific Aim 3, I will attempt to rescue HBsAg seroclearance by bypassing defects in CD4+ T cell priming or treating mice with agonistic antibodies that target T cell co-stimulatory pathways identified in our preliminary investigations. By synergistically analyzing data from our mouse model and human clinical trial, my research aims to provide comprehensive insights into the intricate immune mechanisms influencing HBV seroclearance. By unraveling these complexities, I seek to identify promising therapeutic avenues that could pave the way for a clinical cure.


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 = $47,203 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/14/2025	NON-COMPETING CONTINUATION	$47,203
														Subtotal = $47,203

Issue Date FY: 2024 ( Subtotal = $47,203 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	5/2/2024	NEW	$0
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	5/2/2024	NEW	$1,280
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/8/2024	NEW	$45,923
														Subtotal = $47,203

Grand Total All Awards = $94,406

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Hepatic Priming of CD4+ T cells Directs Effective Hepatitis B Virus Immunity

Award Number: F31DK135386

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/15/2024

PERIOD OF PERFORMANCE END DATE: 03/14/2027

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