Immune Activation, Immunosenescence, and Osteoprotegerin as Markers of Endothelial Dysfunction in Subclinical HIV-Associated Atherosclerosis

HIV-infected patients have a significantly greater risk of cardiovascular disease. Several markers including osteoprotegerin have been shown to be involved in the development and progression of atherosclerosis. We investigated the relationship between T-cell phenotype, osteoprotegerin, and atherosclerosis evaluated by carotid intima-media thickness (c-IMT) in 94 HIV+ patients on suppressive antiretroviral therapy with Framingham score <10%. As for the control group, 24 HIV-negative subjects were enrolled. c-IMT was assessed by ultrasound. CD4+/CD8+ T-cell activation (CD38+ HLADR+) and senescence (CD57+ CD28−) were measured by flow cytometry. IL-6 and OPG levels were measured by ELISA kit. c-IMT was higher in HIV+ than in controls. Among HIV+ patients, 44.7% had pathological c-IMT (≥0.9 mm). CD8+ T-cell activation and senescence and OPG plasma levels were higher in HIV+ patients than in controls. Subjects with pathological c-IMT exhibited higher CD8+ immune activation and immunosenescence and OPG levels than subjects with normal c-IMT. Multivariate analysis showed that age, CD8+ CD38+ HLADR+, and CD8+ CD28− CD57+ were independently associated with pathological c-IMT. Several factors have been implicated in the pathogenesis of atherosclerosis in HIV patients. Immune activation and immunosenescence of CD8+ T cell together with OPG plasma levels might be associated with the development and progression of early atherosclerosis, even in the case of viral suppression.

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The Effect of Rosuvastatin on Markers of Immune Activation in Treatment-Naive Human Immunodeficiency Virus-Patients

Open Forum Infectious Diseases ◽

10.1093/ofid/ofv201 ◽

2015 ◽

Vol 3 (1) ◽

Cited By ~ 6

Author(s):

Robyn G. M. Weijma ◽

Eric R. A. Vos ◽

Jaap Ten Oever ◽

Muriel Van Schilfgaarde ◽

Lea M. Dijksman ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

T Cell Activation ◽

Immune Activation ◽

Cell Activation ◽

Cd8 T Cell ◽

Activation Markers ◽

Cell Ratio ◽

Immunodeficiency Virus ◽

Treatment Naïve

Abstract Background. Immune activation has been implicated in the excess mortality in human immunodeficiency virus (HIV)-infected patients, due to cardiovascular diseases and malignancies. Statins may modulate this immune activation. We assessed the capacity of rosuvastatin to mitigate immune activation in treatment-naive HIV-infected patients. Methods. In a randomized double-blind placebo-controlled crossover study, we explored the effects of 8 weeks of rosuvastatin 20 mg in treatment-naive male HIV-infected patients (n = 28) on immune activation markers: neopterin, soluble Toll-like receptor (TLR)2, sTLR4, interleukin (IL)-6, IL-1Ra, IL-18, d-dimer, highly sensitive C-reactive protein, and CD38 and/or human leukocyte antigen-DR expression on T cells. Baseline data were compared with healthy male controls (n = 10). Furthermore, the effects of rosuvastatin on HIV-1 RNA, CD4/CD8 T-cell count, and low-density lipoprotein cholesterol were examined and side effects were registered. Results. T-cell activation levels were higher in patients than in controls. Patients had higher levels of circulating IL-18, sTLR2, and neopterin (all P < .01). Twenty patients completed the study. Rosuvastatin increased the CD4/CD8 T-cell ratio (P = .02). No effect on other markers was found. Conclusions. Patients infected with HIV had higher levels of circulating neopterin, IL-18, sTLR2, and T-cell activation markers. Rosuvastatin had a small but significant positive effect on CD4/CD8 T-cell ratio, but no influence on other markers of T-cell activation and innate immunity was identified (The Netherlands National Trial Register [NTR] NTR 2349, http://www.trialregister.nl/trialreg/index.asp).

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Persistently high levels of immune activation and their correlation with the HIV-1 proviral DNA and 2-LTR circles loads, in a cohort of Mexican individuals following long-term and fully suppressive treatment.

10.21203/rs.2.21753/v1 ◽

2020 ◽

Author(s):

Aurelio Orta-Resendiz ◽

Monica Viveros-Rogel ◽

Luis L Fuentes-Romero ◽

Moises Vergara-Mendoza ◽

Damaris P Romero-Rodriguez ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Immune Activation ◽

Cell Activation ◽

Cd8 T Cell ◽

Chronic Patients ◽

Ki 67 ◽

Proviral Dna

Abstract Background The main cause of the persistently high levels of immune activation in HIV positive patients undergoing suppressive chronic cART is still unknown. Previous findings have suggested a link between ongoing residual viral replication originating from the HIV reservoir and the immune activation levels. However, there is no clear evidence of this assumption. The aim of this study was to investigate the correlation between the reservoir and the levels of immune activation in chronic patients under fully suppressive cART. Methods We conducted a prospective longitudinal study in a cohort of HIV positive patients undergoing cART for more than 5 years without any documented blips. We quantified the HIV proviral DNA and the 2-LTR circles loads from PBMCs, the levels of immune activation and proliferation markers of T-cells (CD38+, Ki-67+), and the levels of plasmatic IL-7 at enrollment and 1-year of follow-up. Correlation analysis and group comparison were performed. Results 29 participants with a median of 8 years (IQR, 6.9-9.4) under suppressive cART were enrolled and successfully followed at 1 year. In this cohort, we found higher levels of CD8+ T-cell activation (CD38+) after 1-year (P = .000). There was a very weak correlation between the levels of immune activation and the proviral DNA of CD4+ T-cell and CD8+ T-cell. The levels of Ki-67+ T-cells declined on time without significant differences, and there was no significant correlation with the proportion of activated T-cells. The plasmatic levels of IL-7 decreased at the follow-up observation (P = .094), but there was no correlation with the levels of immune activation either. Conclusions We found a weak correlation of the levels of CD4+ and CD8+ T-cell activation with the proviral DNA and 2-LTR circles. This suggests the likely occurrence of further mechanisms driving chronic versus early immune activation other than viral replication by itself in subjects under chronic suppressive cART. More importantly, we highlight the relevance of decreasing T-cell activation in chronic patients to lower the risk of morbidity and early mortality by investigating other activation pathways in specifically chronic phases.

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Faculty Opinions recommendation of Human CD4+CD25+ regulatory cells have marked and sustained effects on CD8+ T cell activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1016400.200702 ◽

2003 ◽

Author(s):

Matthias von Herrath

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cd8 T Cell ◽

Regulatory Cells ◽

Sustained Effects

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Faculty Opinions recommendation of Distinct pathways of antigen uptake and intracellular routing in CD4 and CD8 T cell activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1082777.535694 ◽

2007 ◽

Author(s):

Eric Denkers

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cd8 T Cell ◽

Antigen Uptake

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T-cell Activation Induces Dynamic Changes in miRNA Expression Patterns in CD4 and CD8 T-cell Subsets

MicroRNA ◽

10.2174/2211536604666150819194636 ◽

2015 ◽

Vol 4 (2) ◽

pp. 117-122 ◽

Cited By ~ 16

Author(s):

Nato Teteloshvili ◽

Katarzyna Smigielska-Czepiel ◽

Bart-Jan Kroesen ◽

Elisabeth Brouwer ◽

Joost Kluiver ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Mirna Expression ◽

Cell Activation ◽

Expression Patterns ◽

Cd8 T Cell ◽

T Cell Subsets ◽

Dynamic Changes

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Alterations in STAT Signaling Dysregulate CD8 T Cell Activation

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2020.12.545 ◽

2021 ◽

Vol 147 (2) ◽

pp. AB151

Author(s):

Jose Campos ◽

Peyton Conrey ◽

Samir Sayed ◽

Tiphanie Vogel ◽

Jennifer Leiding ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cd8 T Cell ◽

Stat Signaling

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Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19

Science Immunology ◽

10.1126/sciimmunol.abf7570 ◽

2021 ◽

Vol 6 (57) ◽

pp. eabf7570

Author(s):

Laura A. Vella ◽

Josephine R. Giles ◽

Amy E. Baxter ◽

Derek A. Oldridge ◽

Caroline Diorio ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Immune Activation ◽

Cell Activation ◽

Vascular Complications ◽

Adult Disease ◽

Vasoactive Medication ◽

Inflammatory Syndrome

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8+ T cells that correlated with the use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8+ T cells in the clinical presentation and trajectory of MIS-C.

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