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Harnessing IL-10 in cART treated SIV infected macaques to restore immunity and to eradicate HIV

Award Number: R37AI141258
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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While current ART has prevented AIDS and reduced HIV-related morbidities and mortality for the majority of infected individuals, a therapeutic regimen able to eradicate or functionally cure HIV infection does not exist. Persistence of HIV in a small pool of latently infected cells remains the major obstacle for HIV eradication largely because the mechanisms that underlie viral persistence are still unknown. Our group has generated significant and convincing results in cART treated HIV infected humans and SIV infected rhesus macaques (RMs) suggesting that Interleukin(IL)-10 plays an important role in the establishment and maintenance of the HIV reservoir by (i) impeding the early antiviral innate and the HIV/SIV specific adaptive immune response and (ii) promoting the differentiation of Tfh and Tr1 cells that are major HIV/SIV reservoirs. The importance of IL-10 in the establishment and maintenance of HIV has prompted Merck to successfully develop a Rhesus form of an anti-human IL-10 Ab that is currently being tested in clinic; administration of this Ab in a proof of concept study to SIV infected RMs was safe and well tolerated; it also recapitulated several of the biological activities of the human Ab as it showed a negative impact on Tfh frequencies which could translate in a smaller reservoir. In this proposal, we will test the hypothesis that neutralization of IL-10 activity systemically and in lymphoid tissues will lead to restoration of cellular immune responses, decreased Tfh and Tr1 numbers, and a decay in HIV reservoir. Biomarkers that predict successful clinical interventions involving anti-IL-10 and leading to HIV eradication are not available. In Aim 1, we will perform an unbiased OMICs integrated approach to identify cell subsets, soluble effector molecules, metabolites and molecular pathways, which underlie the modulation of HIV reservoirs by IL-10 in cell subsets isolated from PBMCs and tissues from cART treated HIV infected subjects. We will identify markers that are associated to low levels of IL-10 and conversely to lower HIV reservoir in Tfh and Tr1 cells and efficient innate antiviral and cell mediated immunity. These markers will be used to monitor the impact of the anti-IL-10 intervention that aims at restoring innate antiviral immunity and cell mediated immunity for HIV eradication. Direct demonstration that IL-10 regulates HIV persistence will be provided by examining the impact of IL-10 blockade on virus persistence in a large study of ART-treated, SIV-infected RMs. Preclinical trial of Aim 2 will allow us to determine the restoration of innate immunity by early IL-10 blockade as this intervention should inhibit the upregulation of NLRX-1, a molecule we have shown to play a critical role in the early HIV/SIV dissemination and conversely in the seeding of the HIV/SIV reservoir. Pre-clinical trial of Aim 3 should allow the restoration of the adaptive immune response by preventing the development of IL-10 producing Tr1 cells; IL-10 blockade will also trigger the HIV/SIV reservoir decay in Tfh cells which depend on IL-10 for their survival and differentiation. Achievement of these goals will lead to the development of a much-needed strategy aimed at eradicating HIV.


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: 2023 ( Subtotal = $793,338 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	7	5/26/2023	EXTENSION WITH OR WITHOUT FUNDS	$793,338
														Subtotal = $793,338

Issue Date FY: 2022 ( Subtotal = $769,644 )
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	001	6	7/7/2022	NON-COMPETING CONTINUATION	$769,644
2022	2020	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	3	11/11/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $769,644

Issue Date FY: 2021 ( Subtotal = $1,649,076 )
2021	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	005	5	8/11/2021	NON-COMPETING CONTINUATION	$761,141
2021	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	004	5	8/6/2021	NON-COMPETING CONTINUATION	$779,171
2021	2020	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	001	4	4/30/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$710,934
2021	2020	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	003	4	7/21/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$402,433
2021	2020	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	002	3	7/21/2021	NON-COMPETING CONTINUATION	$262,132
2021	2020	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	3	4/30/2021	NON-COMPETING CONTINUATION	-$461,869
														Subtotal = $1,649,076

Issue Date FY: 2020 ( Subtotal = $836,452 )
2020	2020	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	3	6/19/2020	NON-COMPETING CONTINUATION	$836,452
														Subtotal = $836,452

Issue Date FY: 2019 ( Subtotal = $838,315 )
2019	2019	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	2	7/17/2019	NON-COMPETING CONTINUATION	$838,315
														Subtotal = $838,315

Issue Date FY: 2018 ( Subtotal = $875,207 )
2018	2018	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	1	6/26/2018	NEW	$875,207
														Subtotal = $875,207

Grand Total All Awards = $5,762,032

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Harnessing IL-10 in cART treated SIV infected macaques to restore immunity and to eradicate HIV

Award Number: R37AI141258

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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