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Effects of CSF1R Blockade on Repopulation of SIV Reservoirs from the CNS to the Periphery After Antiretroviral Therapy Interruption

Award Number: R01NS126091
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Despite effective anti-retroviral therapy (ART) that maintains HIV at non-detectable levels in plasma, HIV is not eradicated. When individuals are off ART, or during viral blips, CNS viral reservoirs can quickly rebound. We and others have found that a population of CNS perivascular macrophages (PVMs) function as a major target for HIV and SIV infection in the CNS, and the viral reservoir that persists with ART. Intracisternal (i.c.) injection of superparamagnetic iron oxide nanoparticles (SPIONs) demonstrate PVMs take up SPIONs within the CNS, accumulate with SIV infection, and traffic out of the CNS where they are found in cervical draining lymph nodes (cLNs), dorsal root ganglia, spleen, and bone marrow. Importantly, SPION-labeled CD163+ macrophages in the cLN can be productively infected with SIV as evidenced by SIV-p27 immunoreactivity. It is our overall hypothesis that an identifiable population of PVMs in the CNS functions as a cellular reservoir of rebound HIV and SIV during ART, and after ART cessation, and these cells can leave the CNS with virus that potentially reseeds the periphery. To test our hypothesis, we propose to use a CNS-penetrant colony-stimulating factor 1 receptor (CSF1R) inhibitor (BLZ945) that ablates these reservoir-reseeding CNS PVM early (3 months after ART initiation) and late (5 months after ART initiation) during ART in virally suppressed macaques, and in animals undergoing ART cessation. We propose to use 2 different fluorescently tagged SPIONs, injected intra-CSF just prior to early and late BLZ945 treatments, in order to define the role of resident and repopulated PVMs to function as a viral reservoir of SIV, and block their ability emigrate with virus. We propose to test our hypothesis with two Specific Aims: Aim 1 will determine the extent to which CSF1R blockade can eradicate SIV in the brain and block lymphatic-dependent reseeding of virus from the CNS to the periphery in the presence of ART; and Aim 2 will determine whether CSF1R blockade can prevent reactivation of SIV reservoirs in the brain and repopulation of viral reservoirs from the CNS to the periphery after ART interruption.


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 = $0 )
2024	2023	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	10/31/2023	NON-COMPETING CONTINUATION	$0
2024	2022	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	11/1/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $704,018 )
2023	2023	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/20/2023	NON-COMPETING CONTINUATION	$704,018
														Subtotal = $704,018

Issue Date FY: 2022 ( Subtotal = $707,745 )
2022	2022	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/13/2022	NON-COMPETING CONTINUATION	$707,745
														Subtotal = $707,745

Issue Date FY: 2021 ( Subtotal = $778,847 )
2021	2021	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/12/2021	NEW	$778,847
														Subtotal = $778,847

Grand Total All Awards = $2,190,610

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Effects of CSF1R Blockade on Repopulation of SIV Reservoirs from the CNS to the Periphery After Antiretroviral Therapy Interruption

Award Number: R01NS126091

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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