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Implications of Immune Checkpoint Expression during Aging for HIV-infected People on ART

De Armas, L;Pallikkuth, S;Rinaldi, S;Pahwa, R;Pahwa, S;

Immune checkpoint molecules regulate T cell responses. In chronic viral infections and cancer, where antigens can persistently stimulate the immune system, immune checkpoint molecules can serve as a barrier to effective immune responses. The role of immune checkpoint molecules in the setting of systemic low grade inflammatory such as Aging and ART-suppressed HIV infection is not known. In this study, we made use of stored samples from the FLORAH cohort of HIV-infected, ART suppressed adults (age range 19-77 yrs.) and age-matched HIV uninfected controls. We measured the expression levels of immune checkpoint molecules: PD-1, LAG-3, TIGIT, TIM-3, and 2B4 on resting CD4 and CD8 T cells and maturation subsets. To determine how expression of these molecules can affect T cell function, we stimulated PBMC with HIV Gag or p09/H1N1 antigen and performed intracellular cytokine staining by multi-parameter flow cytometry. Immune checkpoint molecules were expressed at higher levels in CD8 compared to CD4. PD-1 was the only molecule that remained significantly higher in HIV-individuals compared to controls. LAG-3 expression increased with age in CD4 and CD8 T cells. 2B4 expression on CD8 T cells was negatively associated with IL-2 production but showed no effect on CD4 T cell function. TIM-3 expression was negatively associated with IL-21 production in CD4 and CD8 T cells and also negatively correlated with flu vaccine responses in HIV negative individuals. Taken altogether, this study demonstrates the marked variation in immune checkpoint molecule expression in T cells among adults and sheds light on the biology of these molecules and their effects on antigen-specific T cell functions. Overall, our results point to TIM-3 as a potential biomarker for immune function in HIV+ individuals on ART.