IL-32Î³ induces the expression of a heart-homing signature on a subset of memory CD4 T-cells with increased permissiveness to HIV-1 infection: a potential role in cardiovascular disease

Title

IL-32Î³ induces the expression of a heart-homing signature on a subset of memory CD4 T-cells with increased permissiveness to HIV-1 infection: a potential role in cardiovascular disease

Presenter

Hardik Ramani

Authors

H. Ramani * (1,2), A. Gosselin (2), M.A. Jenabian (3), M. Durand (4,2), C. Chartrand-Lefebvre (5,2), N. Chomont (1,2), J.-P. Routy (6), R. Thomas (7), B. Trottier (8), A. Landay (9), P. Ancuta (1,2), M. El-Far (2), C. Tremblay (1,2)

Institutions

(1) Université de Montréal, Département de microbiologie, infectiologie et immunologie, Montreal, Canada, (2) Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada, (3) Université du Québec, Montréal (UQAM), Department of Biological Sciences, Montréal, Canada, (4) Université de Montréal, Département de Médecine, Montréal, Canada, (5) Université de Montréal, Département de Radiologie, Radio-oncologie et Médecine Nucléaire, Montréal, Canada, (6) Research Institute of McGill University Health Centre, Montréal, Canada, (7) Clinique Médicale l'Actuel, Montréal, Canada, (8) Centre de Médecine Urbaine du Quartier Latin, Montréal, Canada, (9) Rush University Medical Center, Department of Internal Medicine, Chicago, United States

BACKGROUND: Chronic inflammation in HIV infection increases the risk of cardiovascular diseases (CVD), even under antiretroviral therapy (ART). We recently demonstrated that the chronic upregulation of the multi-isoform proinflammatory cytokine interleukin-32 (IL-32) is associated with increased CVD risk in people living with HIV (PLWH) receiving ART. IL-32 isoforms exhibit diverse roles in T-cell differentiation, functions, and migration. However, the effect of IL-32 on T-cell heart-tropism, a mechanism that contributes to plaque formation, remains unknown. Here, we investigated the impact of IL-32 isoforms on the induction of the heart-homing signature c-Met+CCR4+CXCR3+ in memory CD4 T-cells in relationship with HIV-DNA persistence in these cells.
METHODS: Peripheral blood mononuclear cells (PBMCs) and plasma samples from ART-treated PLWH and non-infected control participants (n=20/group) were obtained from the Canadian HIV and Aging Cohort Study (CHACS). PBMCs were exposed to 500ng/ml of recombinant IL-32 isoforms (a, Î² and Î³). Expression of c-Met, CCR4, and CXCR3 was measured by flow cytometry on CD4 T-cell subsets.Hepatocyte growth factor (HGF;c-Met ligand) was quantified by ELISA in plasma. Integrated HIV-DNA was quantified by Alu real-time PCR in sorted central memory CD4 T-cell from ART-naïve individuals (n=5, average CD4 counts: 557 cells/ml, and plasma viral load: 109,257 HIV RNA copies/ml).
RESULTS: Among the three IL-32 isoforms tested, stimulation of PBMCs with IL-32Î³ increased the frequency of double-positive (DP) CXCR3+CCR4+ memory CD4 T-cells (n=11, p=0.007). Interestingly, DP cells isolated from ART-naïve HIV+ individuals harboured significantly higher levels of integrated HIV-DNA compared to their double negative or single positive counterparts. Additionally, the DP subset was enriched in cells expressing c-met, indicative of an IL-32-mediated increase in the frequency of the heart-homing triple-positive cMet+CCR4+CXCR3+ population. Finally, we observed that the c-met ligand HGF was significantly higher in plasma from PLWH compared to HIV-individuals (p=0.0009).
CONCLUSIONS: Our results suggest that IL-32 is contributing to heart inflammation by increasing the frequency of T-cells with heart-homing tropism that harbour proviral HIV-DNA. These cells may serve as a Trojan horse to bring HIV to the plaque-forming sites in heart arteries, which could further worsen the local inflammation. Thus IL-32 might represent a potential therapeutic target in CVD.

Download the e-Poster (PDF)