Cytomegalovirus Coinfection Is Associated with Increased Vascular-Homing CD57+ CD4 T Cells in HIV Infection

Abstract

Cytotoxic CD4 T cells are linked to cardiovascular morbidities and accumulate in both HIV and CMV infections, both of which are associated with increased risk of cardiovascular disease (CVD). In this study, we identify CMV coinfection as a major driver of the cytotoxic phenotype, characterized by elevated CD57 expression and reduced CD28 expression, in circulating CD4 T cells from people living with HIV infection, and investigate potential mechanisms linking this cell population to CVD. We find that human CD57 + CD4 T cells express high levels of the costimulatory receptor CD2 and that CD2/LFA-3 costimulation results in a more robust and polyfunctional effector response to TCR signals, compared with CD28-mediated costimulation. CD57 + CD4 T cells also express the vascular endothelium-homing receptor CX3CR1 and migrate toward CX3CL1-expressing endothelial cells in vitro. IL-15 promotes the cytotoxic phenotype, elevates CX3CR1 expression, and enhances the trafficking of CD57 + CD4 T cells to endothelium and may therefore be important in linking these cells to cardiovascular complications. Finally, we demonstrate the presence of activated CD57 + CD4 T cells and expression of CX3CL1 and LFA-3 in atherosclerotic plaque tissues from HIVuninfected donors. Our findings are consistent with a model in which cytotoxic CD4 T cells contribute to CVD in HIV/CMV coinfection and in atherosclerosis via CX3CR1-mediated trafficking and CD2/LFA-3-mediated costimulation. This study identifies several targets for therapeutic interventions and may help bridge the gap in understanding how CMV infection and immunity are linked to increased cardiovascular risk in people living with HIV infection.

CX3CL1 and IL-15 Promote CD8 T cell chemoattraction in HIV and in atherosclerosis

“…Our data suggest a central role for TNF in endothelial dysfunction and vascular disease. This is consistent with the literature-TNF is upregulated in atherosclerosis [50,51], is a major activator of endothelial cells in vitro [15,33,[52][53][54], and a recent meta-analysis has found that pharmacological targeting of TNF appears to be associated with reduced cardiovascular events in patients with rheumatoid arthritis [55,56]. In addition, plasma levels of soluble TNF receptor (sTNFR)-I and sTNFR-II, which are in vivo markers of TNF activity, highly predict the development of cardiovascular morbidities in PLWH [57].…”

“…This difference was also seen with plaque and blood effector memory CD8 T cells in the Moscow cohort ( Fig 2I), suggesting that plaque-derived CD57+ CD8 T cells may have been recently exposed to CX3CL1 which we propose targets them to the plaque in vivo. We recently observed similar evidence for activation and CX3CL1 exposure in plaque-infiltrating CD4 T cells [33].…”

“…CX3CL1, IL-15 and CD8 T cells link HIV and atherosclerosis reports [15,33], but not by HAoSMCs (Fig 5A). TNF has also been shown to elicit IL-15 expression by human umbilical vein ECs [38], and similarly, we found that TNF could induce IL-15 secretion by both HAoECs and HAoSMCs.…”

“…To further test our model, we used an ex vivo transmigration assay system that we recently developed [33] to determine if dysfunctional endothelium could promote the migration of activated CX3CR1+ CD8 T cells. Because exposure to CX3CL1 downmodulates CX3CR1 expression ( Fig 2G), we used CD57 on the surface of CD8 T cells as a marker to identify cells that are or were recently CX3CR1+ [32].…”

Digital spatial profiling of coronary plaques from persons living with HIV reveals high levels of STING and CD163 in macrophage enriched regions

“…Further, a recent publication using single cells isolated from carotid plaque samples of HIV-negative individuals, showed expression of CX3CL1 in nascent plaque and CX3CR1 + CD57 + CD4 + T cells within the plaque by flow cytometry. 27 They did not include plaque from HIV-positive samples which we address in this study.…”