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Host factors regulating HIV latency and reactivation

Award Number: R37AI165137
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: 11/01/2021
PERIOD OF PERFORMANCE END DATE: 10/31/2026

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Host factors regulating HIV latency and reactivation - Abstract Our central premise is that HIV transcriptional inhibitors can be used as latency promoting agents (LPAs) in block-and-lock functional cure approaches, aimed at reducing residual viremia during antiretroviral therapy (ART) and limiting viral rebound upon treatment interruption (TI). This hypothesis came about with the discovery of the Tat inhibitor, didehydro-Cortistatin A (dCA). In in vitro and in vivo models of HIV latency combining ART with dCA accelerated HIV-1 suppression to below the limit of detection and blocked viral rebound upon TI or stimulation with latency reversing agents (LRAs). The transcriptional shutdown by dCA resulted in the heterochromatinization and loss of RNAPII at the HIV promoter. We recently reported on another LPA, the generic drug Spironolactone (SP). Interestingly this drug degrades the host XPB subunit of the general transcription factor TFIIH inhibiting HIV transcription in primary cells from infected individuals and blocking viral reactivation from latency without affecting cellular transcriptomics7. This study is important because it highlights that a host factor can be targeted to silence HIV without affecting cellular viability. In sum, the more knowledge we gain on the interconnectivity between Tat, transcription factors regulatory mechanisms and how these affect nucleosomes positioning around the HIV promoter, the more we can leverage transcriptional regulators as antiviral targets. To identify novel host factors regulating HIV transcription we used a chromatin affinity purification approach together with mass spectrometry (ChAP-MS). We identified p32 (ASF/SF2 splicing factor-associated protein) and FUBP3 (Far upstream element binding protein 3) in productively infected ART treated promoters but not in dCA-treated where HIV was silenced; and PHB2 (prohibitin-2) was enriched in dCA treated promoters but reduced in ART only treated ones. These results suggest that p32 and FUBP3 are HIV transcriptional activators while PHB2 is a HIV silencing factor. Preliminary studies confirmed their transcriptional activity on HIV. Here we propose a detailed molecular mechanistic study on how p32 and FUBP3 enhance and how PHB2 inhibits HIV transcription. Understanding their role in pre-initiation complex (PIC) formation, initiation, elongation and nucleosome organization at the latent HIV promoter will be key for developing successful strategies for durable HIV silencing. Strong effects of one or more of these factors will prompt the search for small-molecule modulators. Our overarching goal is to durably silence latent HIV proviruses by driving each into stable heterochromatin where they will remain “locked.” We propose the following aims: Aim 1: Define the roles of p32, FUBP3 and PHB2 in HIV transcription and chromatin structure. Aim 2: Identify protein complexes associated with p32, FUBP3 and PHB2 and study interaction with Tat. Aim 3: Investigate the “block-and-lock” approach using single or combinations of factors and their dependence on Tat/TAR circuitry.


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 = $468,510 )
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	5	10/30/2024	NON-COMPETING CONTINUATION	$468,510
														Subtotal = $468,510

Issue Date FY: 2024 ( Subtotal = $483,000 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	4	10/23/2023	NON-COMPETING CONTINUATION	$434,700
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	4	5/14/2024	NON-COMPETING CONTINUATION	$48,300
														Subtotal = $483,000

Issue Date FY: 2023 ( Subtotal = $483,125 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	002	3	12/9/2022	NON-COMPETING CONTINUATION	$500
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	3	11/2/2022	NON-COMPETING CONTINUATION	$482,500
2023	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	2	12/8/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$125
														Subtotal = $483,125

Issue Date FY: 2022 ( Subtotal = $256,190 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	003	2	8/31/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$135,564
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	2	8/9/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	2	5/25/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$120,625
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	002	2	8/29/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1
														Subtotal = $256,190

Grand Total All Awards = $1,690,825

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Host factors regulating HIV latency and reactivation

Award Number: R37AI165137

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: 11/01/2021

PERIOD OF PERFORMANCE END DATE: 10/31/2026

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