Role of IL-32 as a predictor and mediator of Premature Aging Phenotypes(PAP) in HIV infection.

Centre Hospitalier De L'Universite De Montreal (University Of Montreal Hospital), Montreal PQ

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Abstract

PROJECT SUMMARY People living with HIV (PLWH) are aging and have increased risk for age-associated health complications such as cardiovascular diseases (CVDs) and low bone mineral density. Both CVD and decreased bone mineral density accelerate frailty, which is a complex of geriatric conditions underlying biological vulnerability and decreased physiological competence that results in multiple adverse outcomes. Inflammation plays a critical role in these ageassociated phenotypes. Identification of novel surrogate inflammatory biomarkers with inherent potential as disease causative agents not only enhances risk stratification in the aging HIV+ populating but also offers important cues for novel therapeutic strategies. IL-32 is a multi-isoform proinflammatory cytokine that we showed to be linked with CVD and aging in HIV infection and is negatively regulated by the gut short chain fatty acid caproic acid. IL-32 is also involved in mechanisms governing bone metabolism, mechanisms that are potentially involved in atherosclerosis. Here, we hypothesize that in HIV infection, IL-32 is involved in Premature Aging Phenotypes (PAP) that are manifested by CVD, altered body composition (low bone mineral density and abnormal fat deposition) and frailty. To validate this hypothesis, our current applications proposes an approach combining in vivo cardiovascular imaging, ex vivo measures of IL- 32 from PLWH for whom frailty and body composition data are available, and in vitro studies intending to investigate the mechanistic link between IL-32 expression and PAP. In Aim 1, we will study the expression of IL-32 isoforms in peripheral blood in PLWH in two large cohorts of men and women; the Canadian HIV and Aging Cohort Study (CHACS) and the Women's Interagency HIV Cohort Study (WIHS), now combined with the Multicenter AIDS Cohort Study (MACS) in the MWCCS cohort, respectively. We will evaluate the potential of IL-32 isoforms in predicting PAP in these two cohorts using two types of analysis; a binary analysis (presence/absence of CVD, frailty and osteoporosis) and joint occurrence of the adverse phenotypes. In Aim 2, we will investigate the mechanisms by which caproic acid regulates IL-32 expression in 3 major cell types; intestinal epithelial cells (as a primary cell types expected to be exposed to caproic acid in gut), CD4 T cells (major cells producing IL-32 and main reservoir for latent HIV under ART) and primary vascular endothelial cells, the dysfunction of which results in frank atherosclerosis. In Aim 3, we further propose to dissect the mechanism(s) by which the CVD-associated IL-32 isoforms impact the process of osteoclastogenesis (differentiation of osteoclast cells involved in bone resorption, lower mineral bone density and potentially the development of noncalcified atherosclerotic lesions). Together, the overarching goal of this project is to demonstrate that IL-32 is a central player in systemic inflammation and an accelerator of multiple aging phenotypes (CVD, frailty and osteoporosis) and that this cytokine can be used as a predictive biomarker for PAP and also as a therapeutic target.