CGC+ CD4+ T Cells are Cytomegalovirus Specific Cells that are Biomarkers of Cardiometabolic Disease Risk in Persons with HIV

Cells of the innate and adaptive immune system are important drivers of cardiometabolic disease in the general population. In persons with HIV (PWH) on antiretroviral therapy, persistent inflammation partly due to coinfection with cytomegalovirus (CMV) may be important. We recently defined a subset of CD4⁺ T cells that co-express three surface markers, CD57, GPR56, and CX3CR1 abbreviated as ‘CGC’. We previously showed that CGC⁺ CD4⁺ T cells are increased with diabetes and a high burden of carotid artery plaque in PWH. In this ongoing study, we use CMV tetramers to define the specificity of CGC⁺ CD4⁺ T cells. In a cohort of non-diabetic, pre-diabetic, and diabetic PWH (n=105), we found that CGC⁺ CD4⁺ T cells in blood were positively correlated with waist circumference (p=0.01), hemoglobin A1C (p=0.002), and fasting blood glucose (p=0.0006) but not cholesterol. Using the select MHC class II tetramers against known immunogenic CMV epitopes, all the CMV-specific T cells were CGC⁺ CD4⁺. We found up to 14-21% of CGC⁺ CD4⁺ T cells recognized a single immunodominant gB epitope – DYSNTHSTRYV (DYS). Multiparameter flow cytometry and mass cytometry analysis showed that CGC⁺ CD4⁺ T cells consist of T effector memory (T_EM) and T effector memory CD45RA (T_EMRA) cells. Other markers co-expressed on CGC⁺ CD4⁺ cells include ICOS⁺, CXCR3^+/-, CD28^+/-,OX40^+/-, and CD27^-. Our findings provide evidence that CGC⁺ CD4⁺ T cells are CMV-specific T cells associated with cardiometabolic disease and could be used to monitor the clinical response to treatments used to reduce inflammation and improve CVD outcomes.