Abstract
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.
Highlights
HIV infection, even when successfully controlled with antiretroviral therapy (ART), upsets the homeostasis of the immune system and is associated with increased morbidities such as cardiovascular disease (CVD) and cancer [1]
Interleukin 6 (IL-6), tumor necrosis factor (TNF), and interleukin 1 beta (IL-1b) are among the earliest cytokines produced during an immune response, but when elevated levels of these cytokines persist they are linked to pathologies associated with chronic inflammation [9]
We found that T cell exhaustion and senescence negatively correlated with levels of TGF-β and positively correlated with plasma levels of induced protein 10 (IP10) and IL-6
Summary
HIV infection, even when successfully controlled with antiretroviral therapy (ART), upsets the homeostasis of the immune system and is associated with increased morbidities such as cardiovascular disease (CVD) and cancer [1]. ART-treated HIV+ people exhibit continued elevation of systemic inflammation as indicated by plasma levels of soluble immune mediators that are associated with non-AIDS morbidities [3,4,5]. Systemic inflammation is prevalent in HIV-uninfected elderly, often referred to as “inflammaging” in those over 65 years old [6]. Chronic elevated plasma levels of soluble immune mediators are associated with morbidities and mortality in HIV-uninfected elderly [7, 8]. Immune non-responders (INR) are HIV+, ART-controlled (>2 yrs) people who fail to reconstitute their CD4 T cell numbers. 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
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