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Role of canonical and non-canonical beta-catenin signaling in HIV-1 latency

Award Number: R15AI172610
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: 08/23/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Role of canonical and non-canonical beta-catenin signaling in HIV-1 latency - PROJECT SUMMARY/ABSTRACT HIV remains an incurable infectious disease due to establishing a subset of latently infected reservoir cells. HIV latent cells are not eradicated by immune systems or combination antiviral therapy (cART) by regulating viral RNA transcription and subsequent protein translations. The long-lived central memory CD4+ T cell subset (TCM) is regarded as the predominant HIV reservoir. Latency reversal agents (LRAs) reactivate dormant viral gene expression, following HIV clearance by immune response or cART. However, the current LRAs have failed to reduce the reservoir size in the clinical trial due to the heterogeneous mechanisms in HIV latency. In addition, LRAs negatively affect immune function. The long-term goal for this research is the identification of alternative pharmaceutical targets to universally influence reverse latency and immune response for HIV functional cure. The Wnt/β-catenin pathway restricts HIV replication and is also involved in HIV latency by promoting self-renewal and proliferation of TCM, while β-catenin is not being explored for HIV latency reversal. The Wnt signal translocates β-catenin to the nucleus that forms a canonical transcriptional complex with the TCF/LEF transcription factors to induce downstream gene expressions (canonical β-catenin signaling). Recently, Interactions of β-catenin with other transcription factors, FOX family proteins, have also been reported, which regulates gene expression independently of canonical β-catenin signaling (non-canonical β-catenin signaling). The rationale of this proposal is based on the previous reports and our preliminary data that 1) inhibition of β-catenin with TCF/LEF complex reactivated HIV latent T cells and immune stimulations, and 2) synergistic latency reversal effect was observed with the HDAC inhibitor by β-catenin attenuation. The objective of this study is to reveal the role of β-catenin signaling pathways in latently infected T cells. The central hypothesis is that the non-canonical β-catenin signaling allows latency reactivation and stimulates immune cell function, which will aid in the design of new strategies for HIV eradication. The objective of this project will be accomplished by three specific aims with a team of undergraduate researchers: 1) Evaluation of non-canonical β-catenin signaling in HIV latency 2) Elucidation of synergistic interaction between LRAs and β-catenin signaling, and 3) Assessment of β-catenin non-canonical signaling in immune activation. The significance of this study is not only finding the novel pathway to let viruses released from latency but also creating a synergistic effect with other LRAs and being an immunostimulant for the subsequent reactivated cell clearance that makes innovation in the successive combination LRA therapy.


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 = $0 )
2025	2022	AMERICAN UNIVERSITY	4400 MASSACHUSETTS AVE NW	WASHINGTON	DC	20016	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	2	6/26/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $3,160 )
2023	2022	AMERICAN UNIVERSITY, THE	4400 MASSACHUSETTS AVE, NW	WASHINGTON	DC	20016	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	001	2	7/12/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$289,015
2023	2022	SAINT JOSEPHS UNIVERSITY	5600 CITY AVE	PHILADELPHIA	PA	19131	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	7/12/2023	NEW	-$285,855
														Subtotal = $3,160

Issue Date FY: 2022 ( Subtotal = $367,500 )
2022	2022	ST JOSEPH'S UNIVERSITY	5600 CITY AVE	PHILADELPHIA	PA	19131	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	8/23/2022	NEW	$367,500
														Subtotal = $367,500

Grand Total All Awards = $370,660

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Role of canonical and non-canonical beta-catenin signaling in HIV-1 latency

Award Number: R15AI172610

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: 08/23/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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