IL-32 Drives the Differentiation of Cardiotropic CD4+ T Cells Carrying HIV DNA in People With HIV

Abstract

IL-32 is a potent multi-isoform proinflammatory cytokine, which is upregulated in people living with HIV (PLWH) and is associated with cardiovascular disease (CVD) risk. However, the impact of IL-32 isoforms on CD4 T-cell cardiotropism, a mechanism potentially contributing to heart inflammation, remains unknown. Here we show that IL-32 isoforms β and γ induce the generation of CCR4 + CXCR3 + double positive (DP) memory CD4 T-cell subpopulation expressing the tyrosine kinase receptor c-Met, a phenotype associated with heart-homing of T-cells. Our ex vivo studies on PLWH show that the frequency of DP CD4 T-cells is significantly higher in individuals with, compared to individuals without, subclinical atherosclerosis and that DP cells from antiretroviral-naïve and treated individuals are highly enriched with HIV DNA. Together, these data demonstrate that IL-32 isoforms have the potential to induce heart-homing of HIV-infected CD4 T-cells, which may further aggravate heart inflammation and CVD in PLWH.