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Understanding HIV latency reversal and clearance of infected cells in vivo

Award Number: R01AI132128
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: 07/21/2017
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Understanding HIV latency reversal and clearance of infected cells in vivo - Project Summary/Abstract: Latently-infected CD4+ T cells are thought to be the main barrier to HIV eradication or functional cure, and viral reactivation from these cells likely contributes to the organ inflammation and damage observed on antiretroviral therapy. Major impediments to the development of more effective latency-reversing agents (LRAs) include the lack of knowledge about the mechanisms that govern latency and latency reversal in vivo, and the degree to which these are recapitulated by latency models in vitro. The lack of agreement between latency models and the incomplete success of human trials with LRAs suggest that it is critical to understand why different LRAs do or do not work in vivo. We have developed a new “transcription profiling” approach that can simultaneously measure the degree to which different mechanisms contribute to reversible inhibition of HIV transcription in vivo. By applying this approach to cells from ART-suppressed patients, we have generated preliminary data suggesting a new paradigm in which latency is not (as commonly assumed) due to a block to HIV transcriptional initiation, the block to proximal elongation is greater and more pervasive than previously realized, and the main reversible blocks to HIV transcription are a previously-unrecognized block to distal transcription/polyadenylation (completion) and a block to multiple-splicing. In addition, we have intriguing new data suggesting that LRAs may act selectively on the different mechanistic blocks to HIV transcription. This study will utilize samples from clinical trials of humans treated with LRAs (aims 1 and 2) to better understand how they reverse the mechanisms of latency in vivo and to identify the optimum model to test new agents in vitro (aim 3). In aim 1, we will apply our transcription profiling approach to samples from humans treated with disulfiram, vorinostat, panobinostat, and romidepsin. We hypothesize that these agents preferentially increase HIV transcriptional initiation and elongation but have less ability to overcome blocks to completion and splicing. In aim 2, we will apply our approach to blood and gut samples from clinical trials of humans treated with agonists of toll-like receptor (TLR) 7 and 9 to understand how these agents reverse latency and lead to death of infected cells in vivo. We hypothesize that TLR agonists can overcome later blocks to HIV transcription, increasing the completed transcripts (and HIV protein/antigen) that may facilitate clearance by intrinsic cell defenses or immune killing. In aim 3, we will compare in vitro models of latency based on the degree to which they recapitulate in vivo mechanisms of latency and responses to LRAs. We will then select the best model and test new combinations of agents for their ability to increase completed/spliced transcripts and lead to death of infected cells. The results from these 3 aims should provide critical new insights on the degree to which existing LRAs reverse the different mechanisms of latency in vivo (aims 1 and 2), the effects that correlate with clearance of reactivated cells (aims 2 and 3), the best system to study LRAs in the laboratory (aim 3), and new combinations that can lead to more effective latency reversal and/or killing of infected cells (aim 3).


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 = -$31,629 )
2025	2021	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST # 151	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	5	2/25/2025	NON-COMPETING CONTINUATION	-$31,629
														Subtotal = -$31,629

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	5	8/11/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $383,250 )
2021	2021	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	5	7/8/2021	NON-COMPETING CONTINUATION	$383,250
														Subtotal = $383,250

Issue Date FY: 2020 ( Subtotal = $383,250 )
2020	2020	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	4	6/26/2020	NON-COMPETING CONTINUATION	$383,250
														Subtotal = $383,250

Issue Date FY: 2019 ( Subtotal = $383,250 )
2019	2019	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	3	7/10/2019	NON-COMPETING CONTINUATION	$383,250
														Subtotal = $383,250

Issue Date FY: 2018 ( Subtotal = $383,250 )
2018	2018	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	2	6/11/2018	NON-COMPETING CONTINUATION	$383,250
														Subtotal = $383,250

Issue Date FY: 2017 ( Subtotal = $383,250 )
2017	2017	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	1	7/21/2017	NEW	$383,250
														Subtotal = $383,250

Grand Total All Awards = $1,884,621

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Understanding HIV latency reversal and clearance of infected cells in vivo

Award Number: R01AI132128

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: 07/21/2017

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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