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Measurement and characterization of CNS and immune tissue myeloid HIV-1 reservoirs

Award Number: R01NS107022
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Measurement and characterization of CNS and immune tissue myeloid HIV-1 reservoirs - Long-lived cells latently infected with HIV-1 form a viral reservoir that cannot be eliminated by current anti-retroviral therapy regimens, even when those therapies are applied over an infected person's lifespan. A comprehensive understanding of cellular and tissue-based reservoirs would facilitate the development of new approaches to eradicate this persistent viral reservoir. We hypothesize that brain and immune tissue macrophage-lineage cells constitute a significant HIV-1 reservoir that is genetically and phenotypically distinct from the CD4+ T cell reservoir. Highly sensitive methods will be used to quantify HIV-1 nucleic acids present in macrophage lineage cells in brain, CSF, and immune tissue and to also determine whether astroglia contribute to a non-T cell reservoir. A key issue is whether macrophage-lineage cells are actually infected, or whether detectable HIV-1 nucleic acids represent ingested or contaminating T cells. Using highly purified macrophages, we will ascertain whether they carry full length, intact proviruses, actively express HIV-1 mRNA, and can produce infectious virus. We will also establish whether macrophage proviruses can be activated ex vivo by latency reversing agents (LRAs). Finally, we will use PacBio next generation sequencing (NGS) and single genome analyses (SGA) to investigate phylogenetic relationships and compartmentalization of HIV-1 in brain, CSF, and immune tissues and in specific cell types i.e. purified macrophages, astroglia and T cells. We propose the following three aims: Aim 1. To measure and characterize the HIV-1 reservoir in macrophages from brain and immune tissue. HIV-1 proviral DNA and mRNA will be quantified in macrophage-lineage cells and T cells purified from brain, CSF, and immune tissue to better understand the number and distribution of cells that are infected and expressing HIV-1 mRNA. Aim 2. To evaluate the presence of replication competent HIV-1 in macrophages from brain and immune tissue. PCR and culture protocols will evaluate whether intact, integrated, replication-competent proviruses are present in macrophages and can be activated with LRAs. Aim 3. To investigate the phylogenetic relationships of HIV-1 in macrophages and T cells in brain and immune tissue. Single genome PCR and PacBio deep sequencing of env and pol genes will be used to investigate the relationships between HIV-1 found in macrophages and T cells in brain, CSF, and immune tissue. Our proposal aims to (1) determine whether macrophages in immune tissue are infected with HIV-1 and form a viral reservoir, (2) set up approaches to quantify infectious HIV-1 proviruses in monocyte/ macrophages in brain, CSF and immune tissue and (3) establish phylogenetic relationships between HIV-1 populations present in purified macrophages and T-cells present in different tissues. Study results will be important for informing strategies to achieve remission, and potential cure, in HIV-1 infected individuals.


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: 2024 ( Subtotal = -$6,249 )
2024	2022	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/17/2024	NON-COMPETING CONTINUATION	-$6,249
														Subtotal = -$6,249

Issue Date FY: 2022 ( Subtotal = $658,712 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/21/2021	NON-COMPETING CONTINUATION	$592,843
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	3/24/2022	NON-COMPETING CONTINUATION	$65,869
														Subtotal = $658,712

Issue Date FY: 2021 ( Subtotal = $658,712 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	1/11/2021	NON-COMPETING CONTINUATION	$65,870
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/16/2020	NON-COMPETING CONTINUATION	$592,842
														Subtotal = $658,712

Issue Date FY: 2020 ( Subtotal = $658,712 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/11/2020	NON-COMPETING CONTINUATION	$65,870
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/31/2019	NON-COMPETING CONTINUATION	$592,842
														Subtotal = $658,712

Issue Date FY: 2019 ( Subtotal = $658,712 )
2019	2019	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/13/2018	NON-COMPETING CONTINUATION	$658,712
														Subtotal = $658,712

Issue Date FY: 2018 ( Subtotal = $652,850 )
2018	2018	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/27/2018	NEW	$652,850
														Subtotal = $652,850

Grand Total All Awards = $3,281,449

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Measurement and characterization of CNS and immune tissue myeloid HIV-1 reservoirs

Award Number: R01NS107022

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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