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Exploring the role of IL-32 as a potential biomarker and therapeutic target in premature cardio-vascular diseases during HIV-infection.

Award Number: R01AG054324
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Introduction of combined anti-retroviral therapy (cART) in the mid 90th has significantly decreased the rate of mortality and enhanced the quality of life of HIV-infected individuals. However as the HIV+ population ages, cardiovascular diseases (CVD) and neurologic complications are increased, which reflects the complex pathophysiological interactions in this population. Identification of early biomarkers that could identify subjects at higher risks for these complications would help better manage aging HIV-infected patients. We have recently identified the over-expression of proinflammatory isoforms of the novel cytokine IL-32 as a robust biomarker that can predict control failure in HIV-infected subjects with a history of slow disease progression. IL-32 is an inflammatory cytokine that induces multiple other inflammatory cytokines such as IL-6, IL-1¿ and TNF¿; all of which are involved in CVD. IL-32 over-expression in vascular tissues is directly associated with CVD. The mechanism(s) behind the over-expression of IL-32 in HIV infection, particularly in treated subjects, remain elusive. IL-32 is part of the innate immune response to viral and bacterial infections and therefore, heightened expression is likely mediated by residual HIV replication under cART but also by other microbial agents that might egress from a dysbiosed gut, weakened in the event of Th17 cell depletion. In this proposal, we aim to demonstrate that over-expression of the proinflammatory isoforms of IL-32 results in cardiac complications that increase with aging. As we showed that IL-32 could robustly predict disease progression in HIV infection several years in advance, we expect to establish the same predictability for cardiac complications. In Specific aim 1, we will take advantage of two large cohorts (The Canadian Cohort of HIV and Aging (CCHA) directed by Dr Cecile Tremblay and the WIHS cohort, directed by our co-applicant Dr Robert Kaplan) to generate a map of expression for the different isoforms of IL-32 in young versus old HIV-infected men and women. We will correlate these measures with a panel of well-established inflammatory biomarkers and subclinical clinical CVD markers such as calcium score, IMT as well as with CVD clinical outcomes. In Specific Aim 2, we will study the interplay between IL-32 expression and HIV reservoirs and residual viremia by comparing young and old groups of HIV infected individuals from the same cohorts. We also aim to study the ability of HIV residual replication to up-regulate IL-32 pro-inflammatory isoforms expression and to down-regulate the less inflammatory ones. In Specific aim 3, we will investigate the impact of intestinal dysbiosis on the induction of IL-32 proinflammatory isoforms by intestinal epithelium. We will also determine the impact of IL-32 production on Th17/Treg ratio at the mucosal and systemic levels in correlation with HIV-related CVD. Together, the overarching goal of this project is to demonstrate that IL-32 is a central player in systemic inflammation and a mediator of CVD and that this cytokine can be used as a predictive biomarker for disease but also as a therapeutic target to modulate inflammatory processes and tackle HIV reservoirs.


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 = $433,719 )
2023	2023	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	850 RUE SAINT-DENIS	MONTREAL	PQ			CAN	Aging Research	001	7	5/10/2023	NON-COMPETING CONTINUATION	$433,719
2023	2020	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	850 RUE SAINT-DENIS	MONTRAAL	QC			CAN	Aging Research	000	5	4/25/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $433,719

Issue Date FY: 2022 ( Subtotal = $439,372 )
2022	2022	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	850 RUE SAINT-DENIS	MONTREAL	PQ			CAN	Aging Research	000	6	7/27/2022	COMPETING CONTINUATION	$439,372
														Subtotal = $439,372

Issue Date FY: 2020 ( Subtotal = $438,200 )
2020	2020	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	850 RUE SAINT-DENIS	MONTREAL	PQ	H2X 0A9		CAN	Aging Research	000	5	6/29/2020	NON-COMPETING CONTINUATION	$438,200
														Subtotal = $438,200

Issue Date FY: 2019 ( Subtotal = $399,411 )
2019	2019	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	850 RUE SAINT-DENIS	MONTREAL	PQ	H2X 0A9		CAN	Aging Research	000	4	6/1/2019	NON-COMPETING CONTINUATION	$399,411
														Subtotal = $399,411

Issue Date FY: 2018 ( Subtotal = $434,974 )
2018	2018	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	850 RUE SAINT-DENIS	MONTREAL	PQ	H2X 0A9		CAN	Aging Research	000	3	6/14/2018	NON-COMPETING CONTINUATION	$434,974
														Subtotal = $434,974

Issue Date FY: 2017 ( Subtotal = $395,625 )
2017	2017	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	3840 RUE SAINT-URBAIN	MONTREAL	PQ	H2W 1T8		CAN	Aging Research	000	2	7/5/2017	NON-COMPETING CONTINUATION	$395,625
														Subtotal = $395,625

Issue Date FY: 2016 ( Subtotal = $433,867 )
2016	2016	UNIVERSITY OF MONTREAL HOSPITAL	3840 ST URBAIN STREET	MONTREAL, QUEBEC				CAN	Aging Research	000	1	9/27/2016	NEW	$433,867
														Subtotal = $433,867

Grand Total All Awards = $2,975,168

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Exploring the role of IL-32 as a potential biomarker and therapeutic target in premature cardio-vascular diseases during HIV-infection.

Award Number: R01AG054324

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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