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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.

Atherosclerotic cardiovascular disease (ASCVD) remains an important cause of morbidity in the general population and risk for ASCVD is increased approximately 2-fold in persons living with HIV infection (PLWH). This risk is linked to elevated CD8 T cell counts that are abundant in atherosclerotic plaques and have been implicated in disease pathogenesis yet the mechanisms driving T cell recruitment to and activation within plaques are poorly defined. Here we investigated the role of CD8 T cells in atherosclerosis in a non-human primate model of HIV infection and in the HIV-uninfected elderly; we sought to identify factors that promote the activation, function, and recruitment to endothelium of CX3CR1+ CD8 T cells. We measured elevated expression of CX3CL1 and IL-15, and increased CD8 T cell numbers in the aortas of rhesus macaques infected with SIV or SHIV, and demonstrated similar findings in atherosclerotic vessels of HIV-uninfected humans. We found that recombinant TNF enhanced the production and release of CX3CL1 and bioactive IL-15 from aortic endothelial cells, but not from aortic smooth muscle cells. IL-15 in turn promoted CX3CR1 surface expression on and TNF synthesis by CD8 T cells, and IL-15-treated CD8 T cells exhibited enhanced CX3CL1-dependent chemoattraction toward endothelial cells in vitro.

Objective Microlaryngeal surgery typically requires oxygenation and ventilation via either an endotracheal tube (ETT), jet ventilation (JV), or intermittent apnea with an ETT. Transnasal Humidified Rapid Insufflation Ventilatory Exchange (THRIVE) delivered by high flow nasal cannula has been reported as an alternative technique. This method of apneic oxygenation and ventilation allows for stable, unobstructed visualization of immobile laryngeal structures. We aim to describe the technique and characterize intraoperative parameters related to its safety. Study Design Case Series. Methods The electronic medical record was reviewed for patients who underwent microlaryngoscopy using THRIVE technique. Patient demographics, procedural details, operative parameters, and anesthesia records were reviewed. Descriptive statistics were reported. Results A total of 53 patients underwent microlaryngoscopy using THRIVE as the sole method of ventilation, with 62% female. Median age was 51 years, and median BMI was 25 kg/m2. Most patients were ASA class 2, and most had a Mallampati score of 2. The most common surgical indications were subglottic stenosis, vocal fold lesions, and vocal fold paralysis. Median apnea time was 16 minutes. At the end of case, median end tidal CO2 was 50 mmHg, and median minimum SpO2 was 95. Six cases required supplementation of THRIVE with JV or tracheal intubation for sustained oxygen desaturation. There was an increase in end tidal CO2 of 0.844 mmHg/min of apneic time. Conclusions THRIVE is a safe and effective technique for oxygenation and ventilation in microlaryngeal, non‐laser surgery in appropriately selected patients. To ensure safety, back‐up plans such as jet ventilation and microlaryngeal ETT should be available. Level of Evidence 4 Laryngoscope, 131:587–591, 2021

Circulating CD8 + T cells and monocytes are activated during human immunodeficiency virus (HIV) infection and colocalize in the aortas of simian immunodeficiency virus-infected nonhuman primates. We hypothesized that CD8 + T cells could exert a proatherosclerotic effect via paracrine actions on monocytes. We found that T-cell receptor-stimulated CD8 + T cells induce monocytes to express tissue factor, a potent activator of coagulation. Tumor necrosis factor was both necessary and sufficient for this effect.

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Cytotoxic CD4 T cells are linked to cardiovascular morbidities and accumulate in both human immunodeficiency virus (HIV) and cytomegalovirus (CMV) infections, both of which are associated with increased risk of cardiovascular disease. Here 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 (PLWH). We find that 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 T cell receptor (TCR) signals, compared to 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, and may therefore be important in linking these cells to cardiovascular complications. Finally, we demonstrate the presence of CD57+ CD4 T cells and expression of IL-15, CX3CL1, and LFA-3 in atherosclerotic plaque tissues from HIV-uninfected donors. Our findings are consistent with a model in which cytotoxic CD4 T cells contribute to cardiovascular disease in HIV/CMV coinfection and in atherosclerosis via CX3CR1-mediated trafficking and CD2-mediated costimulation, and may help bridge the gap in understanding how CMV infection and immunity are linked to increased cardiovascular risk in PLWH.