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A murine model for HIV/AIDS associated cryptococcal IRIS: characterizing the molecular mechanism of CD4+ T cell migration to the brain

Award Number: R21AI186685
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: 11/19/2024
PERIOD OF PERFORMANCE END DATE: 10/31/2026

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A murine model for HIV/AIDS associated cryptococcal IRIS: characterizing the molecular mechanism of CD4+ T cell migration to the brain - Project Summary A hallmark of HIV-infection is the progressive depletion of CD4+ T cells, which renders HIV/AIDS patients more susceptible to infection with opportunistic pathogens such as the encapsulated fungus Cryptococcus neoformans. C. neoformans is a leading cause of mortality of HIV/AIDS patients and accounts for approximately 112,000 deaths worldwide annually. Antiretroviral therapy (ART) is a major advance in treating HIV/AIDS patients by restoring cellular immune responses including CD4+ T cell response. However, a rapid reconstitution and migration of CD4+ T cells to the brain in HIV/AIDS patients with cryptococcosis after initiation of ART frequently leads to immune reconstitution inflammatory syndrome (IRIS), an aberrant excessive immune response that is life-threatening with a mortality of 33% to 66%. Thus, CD4+ T cells play a central role in the aberrant lethal immune responses during HIV/AIDS associated cryptococcal IRIS. A critical gap in our understanding of cryptococcal IRIS remains: what is the molecular mechanism(s) of CD4+ T cell migration to the brain? TNF-α is a major biomarker of HIV/AIDS associated cryptococcal IRIS. However, how TNF-α contributes to cryptococcal IRIS is unknown. Based on our preliminary studies, we hypothesize that TNF-α signals directly on CD4+ T cells in a cell-intrinsic manner and drives CD4+ T cell migration to the brain through enhanced CD11a expression on CD4+ T cells during cryptococcal IRIS. Recently, a robust and physiologically relevant murine model of HIV/AIDS associated cryptococcal IRIS has been developed. This murine model of C. neoformans brain infection reproduces key aspects of cryptococcal IRIS of HIV/AIDS patients. Using this murine model, we will test our hypothesis by addressing the following aims: 1) To determine whether TNF-α signaling mediates CD4+ T cell migration to the brain in a cell-intrinsic manner during cryptococcal IRIS; and 2) To determine whether CD11a signaling is critically involved in CD4+ T cell migration to the brain in a cell-intrinsic manner during cryptococcal IRIS. If successful, the findings of this study would be fundamental for understanding HIV/AIDS associated cryptococcal IRIS and provide scientific basis for targeting TNF-α and CD11a signaling as a therapeutic strategy of cryptococcal IRIS.


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 = $231,134 )
2026	2026	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	2	11/26/2025	NON-COMPETING CONTINUATION	$231,134
														Subtotal = $231,134

Issue Date FY: 2025 ( Subtotal = $186,451 )
2025	2025	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	001	1	8/12/2025	NEW	$0
2025	2025	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	1	11/19/2024	NEW	$186,451
														Subtotal = $186,451

Grand Total All Awards = $417,585

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A murine model for HIV/AIDS associated cryptococcal IRIS: characterizing the molecular mechanism of CD4+ T cell migration to the brain

Award Number: R21AI186685

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: 11/19/2024

PERIOD OF PERFORMANCE END DATE: 10/31/2026

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