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Novel single genome approaches to determine the mechanisms of HIV latent infection in blood, gut, and lymph nodes

Award Number: R01DK120387
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Novel single genome approaches to determine the mechanisms of HIV latent infection in blood, gut, and lymph nodes - 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 may contribute to the organ inflammation and damage observed on antiretroviral therapy. A major impediment to the development of more effective therapies for HIV, including those aimed at cure, is the lack of knowledge about the mechanisms that govern latent HIV infection in vivo. We have developed a new “transcription profiling” approach that can simultaneously measure the degree to which different mechanisms inhibit HIV transcription in vivo. By applying this approach to cells from ART-suppressed patients, we found that a series of blocks to HIV transcriptional elongation, distal transcription/polyadenylation (completion), and multiple splicing are the main mechanisms that reversibly suppress virus production in the blood. In contrast, HIV-infected cells in the rectum showed a strong and paradoxical block to initiation of HIV transcription. A critical unanswered question is whether the same or different mechanisms operate in the small subset of cells with infectious proviruses, which constitute the true latent reservoir. In aims 1-3 of this proposal, we will determine the degree to which different mechanisms reversibly block virus production in individual patient cells with intact or defective proviruses by using a novel approach that combines both single genome “whole provirus” sequencing and single genome HIV transcription profiling. In aim 1, we will apply these methods to blood CD4+ T cells from ART-suppressed patients to determine the degree to which different mechanisms constitutively inhibit HIV transcription in blood CD4+ T cells with intact or defective proviruses, the degree to which they are reversed by short term T cell activation ex vivo, and the degree to which they differ in activated cells that do and do not produce supernatant virus. In aim 2, we will extend these studies to PD-1+ and PD-1- CD4+ T cells from blood, lymph node, and gut to determine whether there are differences by tissue or PD-1 expression in proviral sequences and the mechanisms that reversibly suppress virus production in individual cells with defective and intact proviruses. Aim 3 will further extend these findings by using a new method that combines single genome “whole provirus” and integration site sequencing, in combination with ATAC-seq, to determine how integration site and chromatin accessibility affect constitutive HIV transcription and reactivation potential in cells with intact and defective proviruses. These 3 aims will help definitively answer the question of what mechanisms govern HIV latency in vivo in the blood and the tissues, which has been a major goal of HIV research for the last 20 years and should help inform new therapies aimed at eradication, functional cure, or reducing the sequelae of treated HIV infection.


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	2023	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST # 151	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/17/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $810,339 )
2023	2023	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/13/2023	NON-COMPETING CONTINUATION	$810,339
														Subtotal = $810,339

Issue Date FY: 2022 ( Subtotal = $810,339 )
2022	2022	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/19/2022	NON-COMPETING CONTINUATION	$810,339
														Subtotal = $810,339

Issue Date FY: 2021 ( Subtotal = $810,339 )
2021	2021	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/22/2021	NON-COMPETING CONTINUATION	$810,339
														Subtotal = $810,339

Issue Date FY: 2020 ( Subtotal = $810,339 )
2020	2020	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/8/2020	NON-COMPETING CONTINUATION	$810,339
														Subtotal = $810,339

Issue Date FY: 2019 ( Subtotal = $836,710 )
2019	2019	NORTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION, INC.	4150 CLEMENT ST 151 NC	SAN FRANCISCO	CA	94121	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/21/2019	NEW	$836,710
														Subtotal = $836,710

Grand Total All Awards = $4,078,066

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Novel single genome approaches to determine the mechanisms of HIV latent infection in blood, gut, and lymph nodes

Award Number: R01DK120387

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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