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=Volume 12 - 2021

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=Abstract
Background: Immune non-responders (INR) are HIV+, ART-controlled (>2yrs) 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-b 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 markersexpression of exhaustion (PD-1, TIGIT) and senescence (CD57, KLRG-1) markers was 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. and was highest in INR. Plasma levels of IL-6, IP10, and sCD14 were elevated during HIV infection. IP10 was higher in INR. Plasma TGF-b levels and CD4 cycling proportions of T regulatory cells were lower in INR. Proportions of CD4 T cells expressing TIGIT, PD-1 and CD57 exhaustion and senescence positively correlated with plasma levels of IP10 and IL-6. Plasma levels of TGF-b  and negatively correlated with proportions of TIGIT+ and PD-1+ T cell subsets.levels of TGF-b.

Conclusions:  INR have lower levels of TGF-b and decreased proportions of cycling CD4 T regulatory cells and may have difficulty controlling inflammation. IP10 is elevated in INR and is linked may contribute to higher proportions of and the resulting increase in T cell exhaustion and senescence seen in INR.