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Regulation and Role of pDC in Immunopathogenesis of HBV/HIV co-Infection

Award Number: R01DK149875
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Regulation and Role of pDC in Immunopathogenesis of HBV/HIV co-Infection - Persons with HIV/HBV coinfection (~8% of 250 million CHB population) have more severe liver disease and immune suppression, which may impose unique challenges to achieving functional cure of CHB infection. We have recently discovered that HIV-induced inflammatory pDC (ipDC) and IFN-I signaling contribute to immune impairment and fibrosis in the liver. We hypothesize that HIV coinfection induces the ipDC/IFN-I pathway to suppress anti-HBV immunity during infection or in response to novel HBV immune therapy. A major hurdle to elucidating mechanisms underlying the HIV-impaired immunity to HBV, and to developing effective therapies, is the lack of small animal models that reproduce human-like immune responses with HBV and HIV infection. We have developed a novel humanized mouse model that supports HBV infection and HBV/HIV coinfection (FNRG-hu HIS/HEP mice). We hypothesize that HIV coinfection induces the pDC/IFN-I pathway to suppress anti-HBV immunity and exacerbate HBV immunopathogenesis. Aim 1 is proposed to study HBV infection and anti-HBV specific immunity in humanized mice +/- HIV coinfection. We aim to determine the mechanism of immune dysregulation during HBV infection without and with HIV coinfection in dually humanized FNRG-hu HIS/HEP mice (Aim 1A). We will also develop a novel complimentary model FNRG-hu HIS/fMHO mice with fetal hepatocytes-derived mature organoid to study HBV/HIV infection with autologous human immune/liver cells (Aim 1B). The effect of HBV +/- HIV on human immune cells will be studied by FACS, functional and multiomics assays. Aim 2 will elucidate how pDC impair HBV-specific immunity in Hu- HIS/HEP mice +/- HIV coinfection. We aim to determine the mechanism of immune dysregulation during HBV infection +/- HIV coinfection in dually humanized HIS/HEP or FNRG-hu HIS/fMHO mice. We will deplete pDC with anti-pDC mAb or reprogram their maturation with pDC-targeted TLR9 agonists. The effect of pDC on human T and B cells will be studied by functional assays and multiomics assays. In Aim 3, we will elucidate how pDC impair HBV-specific immunity in PBMC from CHB +/- HIV coinfection ex vivo. With PBMCs from HBV patients +/- HIV infection, we will evaluate the impact of modulating pDC on HBV-specific immune impairment and rescue the function of HBV-specific T and B cells. We will study functional impairments by the HIV-pDC axis in PBMCs from HBV patients +/- HIV infection by functional assays and multiomics assays. The proposed work uses innovative humanized mouse models for HBV/HIV co-infection, as well as PBMC samples from persons with HIV/HBV infected patients, to answer critical questions related to HIV/HBV- impaired immune functionality in HBV cure. Our work will advance the field of HIV/HBV coinfection and immunopathogenesis. Most importantly, the findings will shed light on developing novel therapeutic approaches to cure HBV and HIV/HBV-induced liver diseases.


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 = $617,553 )
2026	2026	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/4/2026	NEW	$617,553
														Subtotal = $617,553

Grand Total All Awards = $617,553

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Regulation and Role of pDC in Immunopathogenesis of HBV/HIV co-Infection

Award Number: R01DK149875

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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