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A Novel Shock-and-Kill with Shield Strategy Targeting HIV Latency and Neuroinflammation in CNS Reservoirs

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: 07/31/2029

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A Novel Shock-and-Kill with Shield Strategy Targeting HIV Latency and Neuroinflammation in CNS Reservoirs - PROJECT SUMMARY/ABSTRACT Despite durable viral suppression with combination antiretroviral therapy (cART), more than half of people living with HIV (PLWH) continue to experience HIV-associated neurocognitive disorders (HAND). A major barrier to preventing HAND is the persistence of latent HIV reservoirs within the central nervous system (CNS), particularly in microglia cells, which are long-lived, difficult to eliminate, and drivers of chronic neuroinflammation and oxidative stress. HIV-associated oxidative toxicity and inflammatory signaling disrupt synaptic function and accelerate cognitive decline, underscoring the need for CNS-directed HIV cure strategies. Building on our original NIH R15–funded work, the Izumi Lab has demonstrated that FDA-approved PARP inhibitors enhance HDAC inhibitor–mediated latency reversal in vitro and promote immune-mediated clearance of reactivated cells. Mechanistically, this synergy involves the inhibition of Hippo signaling regulated by tankyrase, a PARP family protein. Inhibition of tankyrase by PARP inhibitors can unleash the full latency- reversing potential of the HDAC inhibitor. We further demonstrated that the PARP inhibitor also enhances NK cell cytotoxic activity, facilitating the elimination of reactivated cells. Importantly, PARP and HDAC inhibitors have also been reported to exhibit antioxidant and anti-inflammatory activities in CNS models, suggesting that brief “shock” dosing to expose latent virus and “kill” strategies to eliminate reactivated cells by inducing immune responses can be paired with a “shield” to blunt ROS- and inflammatory cytokine-driven neurotoxicity during reactivation. The overall objective of this renewal proposal is to further validate combination therapy with PARP and HDAC inhibitors as part of a “shock-and-kill with shield” strategy that integrates HIV latency reservoir reduction with preservation of CNS integrity in vitro (SA1) and in vivo (SA2). We will evaluate drug efficacy in SA1 using several microglial cell lines, including human microglial (C20 and HMC3-CD4), the rat microglial (CHME-5), the mouse microglial (BV2) cell lines, and primary monocyte-derived microglia-like cells (MDMi). We will further assess the potency of drug combinations in SA2 in vivo using an EcoHIV mouse model to quantify CNS and peripheral reservoir size, microglial activation, neuroinflammation, and neurocognitive outcomes following short-course combination therapy with clinically relevant doses of PARP and HDAC inhibitors. CNS and peripheral blood reservoir sizes will be assessed by molecular virology techniques such as qRT-PCR, flow cytometry, and fluorescence microscopy. Neurocognitive impairments will be evaluated using a combination of molecular virology, biochemical assays, and behavioral readouts to link reservoir reduction with functional benefit, while supporting undergraduate training central to the R15 mechanism. Successful completion of this project will provide mechanistic and preclinical validation of a dual-function therapeutic paradigm that integrates HIV cure strategies with neuroprotection, advancing translational approaches to reduce viral reservoirs in both the CNS and periphery and to improve long-term cognitive health in PLWH. 1


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 = $513,946 )
2026	2026	AMERICAN UNIVERSITY	4400 MASSACHUSETTS AVE NW	WASHINGTON	DC	20016	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	3	7/21/2026	COMPETING CONTINUATION	$513,946
														Subtotal = $513,946

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 = $884,606

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A Novel Shock-and-Kill with Shield Strategy Targeting HIV Latency and Neuroinflammation in CNS Reservoirs

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: 07/31/2029

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