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

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

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.638010

DOI=10.3389/fimmu.2021.638010

ISSN=1664-3224

ABSTRACT=<p><bold>Background:</bold> Immune non-responders (INR) are HIV+, ART-controlled (&gt;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 &lt;50 years old to control for the confounder of older age.</p><p><bold>Methods:</bold> 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 (<italic>n</italic> = 63). Immune parameters were also measured in HIV-uninfected, age distribution-matched controls (HC; <italic>n</italic> = 30). Associations between T cell markers of exhaustion and senescence and plasma levels of immune mediators were examined by Spearman rank order statistics.</p><p><bold>Results:</bold> 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.</p><p><bold>Conclusions:</bold> 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.</p>