Journal Article

Markers of T Cell Exhaustion and Senescence and Their Relationship to Plasma TGF-β Levels in Treated HIV+ Immune Non-responders

Anthony, Donald D., Freeman, Michael L., Younes, Souheil-Antoine, Lederman, Michael M., Kowal, Corinne M., Canaday, David H., Rodriguez, Benigno, Shive, Carey L.

2021

Overview

Background: Immune non-responders (INR) are HIV+, ART-controlled (>2 yrs) people who fail to reconstitute their CD4 T cell numbers. Systemic inflammation and markers of T cell senescence and exhaustion are observed in INR. This study aims to investigate T cell senescence and exhaustion and their possible association with soluble immune mediators and to understand the immune profile of HIV-infected INR. Selected participants were <50 years old to control for the confounder of older age. Methods: Plasma levels of IL-6, IP10, sCD14, sCD163, and TGF-β and markers of T cell exhaustion (PD-1, TIGIT) and senescence (CD57, KLRG-1) were measured in ART-treated, HIV+ participants grouped by CD4 T cell counts ( n = 63). Immune parameters were also measured in HIV-uninfected, age distribution-matched controls (HC; n = 30). Associations between T cell markers of exhaustion and senescence and plasma levels of immune mediators were examined by Spearman rank order statistics. Results: Proportions of CD4 T cell subsets expressing markers of exhaustion (PD-1, TIGIT) and senescence (CD57, KLRG-1) were elevated in HIV+ participants. When comparing proportions between INR and IR, INR had higher proportions of CD4 memory PD-1+, EM CD57+, TEM TIGIT+ and CD8 EM and TEM TIGIT+ cells. Plasma levels of IL-6, IP10, and sCD14 were elevated during HIV infection. IP10 was higher in INR. Plasma TGF-β levels and CD4 cycling proportions of T regulatory cells were lower in INR. Proportions of CD4 T cells expressing TIGIT, PD-1, and CD57 positively correlated with plasma levels of IL-6. Plasma levels of TGF-β negatively correlated with proportions of TIGIT+ and PD-1+ T cell subsets. Conclusions: INR have lower levels of TGF-β and decreased proportions of cycling CD4 T regulatory cells and may have difficulty controlling inflammation. IP10 is elevated in INR and is linked to higher proportions of T cell exhaustion and senescence seen in INR.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Acquired immune deficiency syndrome / Adult / Age / Age composition / AIDS / Anti-Retroviral Agents - therapeutic use / Antigens, CD - blood / Antigens, Differentiation, Myelomonocytic - blood / Antiretroviral therapy / Biomarkers - blood / CD4 antigen / CD4 Lymphocyte Count / CD4-Positive T-Lymphocytes - immunology / CD57 antigen / CD57 Antigens - blood / CD8 antigen / Cell cycle / Cellular Senescence - immunology / Cloning / Cytokines / Disease / exhaustion / Female / HIV / HIV Infections - immunology / HIV+ immune non-responders / Human immunodeficiency virus / Humans / Immunology / Immunoregulation / Inflammation / Interleukin 6 / Interleukin-6 - blood / Lectins, C-Type - blood / Ligands / Lipopolysaccharide Receptors - blood / Lymphocyte Activation - immunology / Lymphocytes / Lymphocytes T / Male / Middle Aged / Monoclonal antibodies / Morbidity / Mortality / PD-1 protein / Plasma / Plasma levels / Programmed Cell Death 1 Receptor - blood / Receptors, Cell Surface - blood / Receptors, Cytokine - blood / Receptors, Immunologic - blood / Review boards / Senescence / T regulatory cells / T-Lymphocyte Subsets - immunology / TGF-β / Transforming Growth Factor beta - blood / Transforming growth factor-b / Tumor necrosis factor-TNF / Viral infections / Young Adult