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Functional Testing of Host Genes that Control HIV Latency in Primary Immune Cells

Award Number: DP2DA042423
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/06/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2021

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Functional Testing of Host Genes that Control HIV Latency in Primary Immune Cells - PROJECT SUMMARY/ABSTRACT HIV infection is effectively controlled for many patients by long-term use of combination therapies that target actively replicating virus. However, currently available therapies do not lead to viral eradication and HIV remains an incurable, chronic condition. For many patients, substance abuse complicates the chronic administration of anti-retrovirals and predisposes to viralogic failure. Vulnerable patients who are unable to consistently use life-long, daily anti-retrovirals urgently need a cure. One promising strategy to eliminate latently infecting cells is “shock and kill,” a strategy that depends on “shocking” latent provirus to an active state so that it can be targeted effectively by medications or host immune factors. However, to effectively drug latently infected cells, we need a deeper understanding of the cellular factors that control viral latency. Functional testing of candidate host factors is critical to understand the mechanisms that control HIV latency. However functional genetic studies in primary human immune cells have been largely impossible until recently. We recently developed a robust CRISPR/Cas9-based technology that enables both ‘knock- out’ and ‘knock-in’ genome editing in primary human T cells. We now propose a comprehensive strategy to test how specific host factors control HIV latency in primary immune cells. The central innovation of this proposal is a high-throughput platform for rapidly generating isogenic human T cells with candidate factors deleted in an arrayed fashion. CRISPR/Cas9 ribonucleoproteins (RNPs) will be transiently delivered to T cells by electroporation to permanently delete targeted genes. This programmable platform will be exploited to rapidly identify and characterize human host factors that regulate multiple stages of the HIV lifecycle. We will focus on elucidating the key genes that control HIV latency and re-activation. Functional assessment of candidates will be performed using a novel HIV dual-fluorescence reporter that can differentiate between latently and productively infected primary T cells. The integration of genome-scale analysis and functional genetics in primary human T cells will accelerate the discovery of novel pathways that regulate HIV infection and latency. Importantly, we will validate the function of these novel regulators of latency using blood samples from HIV-infected patients with substance abuse. These studies are designed to develop targets for a new generation of HIV therapeutics aimed at eradicating latent virus from patients.


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: 2021 ( Subtotal = -$1 )
2021	2016	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Drug Use and Addiction Research Programs	006	2	9/27/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$1
2021	2016	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Drug Use and Addiction Research Programs	001	2	1/22/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$182,413
2021	2016	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Use and Addiction Research Programs	000	1	1/22/2021	NEW	-$182,413
2021	2016	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Drug Use and Addiction Research Programs	004	2	3/8/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2021	2016	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Drug Use and Addiction Research Programs	003	2	2/21/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1
2021	2016	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Use and Addiction Research Programs	002	1	2/21/2021	NEW	-$1
2021	2016	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Drug Use and Addiction Research Programs	005	2	4/7/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = -$1

Issue Date FY: 2016 ( Subtotal = $2,377,500 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Use and Addiction Research Programs	000	1	5/31/2016	NEW	$2,377,500
														Subtotal = $2,377,500

Grand Total All Awards = $2,377,499

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Functional Testing of Host Genes that Control HIV Latency in Primary Immune Cells

Award Number: DP2DA042423

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/06/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2021

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