IL-32γ 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


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, β and γ). 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-32γ 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.

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