Short- and Long-Term Immunological Responses in Chronic HCV/HIV Co-Infected Compared to HCV Mono-Infected Patients after DAA Therapy

Background: Direct-acting antivirals (DAAs) treatment, although highly efficacious for the treatment of hepatitis C virus (HCV) infection, may not completely reconstitute the HCV-mediated dysregulated immune system, especially in patients co-infected with human immunodeficiency virus (HIV) and HCV. Objectives: We aimed to evaluate the impact of HCV eradication following DAA therapy on the immune system and liver disease improvement through comparative monitoring of 10 HCV mono-infected and 10 HCV/HIV co-infected patients under combined antiretroviral therapy (cART). Early and late longitudinal phenotypic changes in peripheral blood mononuclear cell (PBMC) subsets, T-cell activation, differentiation and exhaustion, as well as inflammatory biomarkers, indoleamine 2-3 dioxygenase (IDO) activity, and liver stiffness, APRI and FIB-4 scores were assessed. Materials and Methods: Samples were obtained at baseline (T0), week 1 (T1), week 2 (T2), week 12 (T3, end of treatment, EOT), and month 9 (T4, end of follow-up, 36 weeks post EOT). Results: All patients achieved a sustained virological response (SVR 12) after DAA treatment. Overall, changes of the T-cell immune phenotypes were greater in HCV/HIV co-infected than in HCV mono-infected, due to an increase in CD4+ and CD8+ T-cell percentages and of CD8+ T-cell activation and memory markers, in particular at the end of follow-up. On the other end, HCV mono-infected showed changes in the activation profile and in the memory CD4+ T-cell compartment. In HCV/HIV co-infected, a decrease in the IDO activity by DAA treatment was observed; conversely, in HCV mono-infected, it resulted unmodified. Regarding inflammatory mediators, viral suppression was associated with a reduction in IP-10 levels, while interferon regulatory factor (IRF)-7, interferon (IFN)-β, and interferon (IFN)-γ levels were downregulated during therapy and increased post therapy. A decrease in liver stiffness, APRI, and FIB-4 scores was also observed. Conclusions: Our study suggests that, although patients achieved HCV eradication, the immune activation state in both HCV mono-infected and HCV/HIV co-infected patients remains elevated for a long time after the end of DAA therapy, despite an improvement of liver-specific outcomes, meanwhile highlighting the distinct immunophenotypic and inflammatory biomarker profile between the groups of patients.

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The impact of age on the prognostic capacity of CD8+ T-cell activation during suppressive antiretroviral therapy

AIDS ◽

10.1097/qad.0b013e32836191b1 ◽

2013 ◽

Vol 27 (13) ◽

pp. 2101-2110 ◽

Cited By ~ 11

Author(s):

Judith J. Lok ◽

Peter W. Hunt ◽

Ann C. Collier ◽

Constance A. Benson ◽

Mallory D. Witt ◽

...

Keyword(s):

T Cell ◽

Antiretroviral Therapy ◽

T Cell Activation ◽

Cell Activation ◽

Cd8 T Cell ◽

The Impact

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CTLA-4 dysregulation of self/tumor-reactive CD8+ T-cell function is CD4+ T-cell dependent

Blood ◽

10.1182/blood-2006-07-034066 ◽

2006 ◽

Vol 108 (12) ◽

pp. 3818-3823 ◽

Cited By ~ 38

Author(s):

Luca Gattinoni ◽

Anju Ranganathan ◽

Deborah R. Surman ◽

Douglas C. Palmer ◽

Paul A. Antony ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Cell Activation ◽

Cell Function ◽

Cd8 T Cell ◽

Peripheral Tolerance ◽

The Impact

AbstractCytotoxic T lymphocyte–associated antigen 4 (CTLA-4) maintains peripheral tolerance by suppressing T-cell activation and proliferation but its precise role in vivo remains unclear. We sought to elucidate the impact of CTLA-4 expression on self/tumor-reactive CD8+ T cells by using the glycoprotein (gp) 100–specific T-cell receptor (TCR) transgenic mouse, pmel-1. pmel-1 CLTA-4–/– mice developed profound, accelerated autoimmune vitiligo. This enhanced autoimmunity was associated with a small but highly activated CD8+ T-cell population and large numbers of CD4+ T cells not expressing the transgenic TCR. Adoptive transfer of pmel-1 CLTA-4–/– CD8+ T cells did not mediate superior antitumor immunity in the settings of either large established tumors or tumor challenge, suggesting that the mere absence of CTLA-4–mediated inhibition on CD8+ T cells did not directly promote enhancement of their effector functions. Removal of CD4+ T cells by crossing the pmel-1 CLTA-4–/– mouse onto a Rag-1–/– background resulted in the complete abrogation of CD8+ T-cell activation and autoimmune manifestations. The effects of CD4+ CLTA-4–/– T cells were dependent on the absence of CTLA-4 on CD8+ T cells. These results indicated that CD8+ CLTA-4–/– T-cell–mediated autoimmunity and tumor immunity required CD4+ T cells in which the function was dysregulated by the absence of CTLA-4–mediated negative costimulation.

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CD8+T cell activation and differentiation in allergic asthma and the impact of cytomegalovirus serological status

Clinical & Experimental Immunology ◽

10.1111/j.1365-2249.2007.03408.x ◽

2007 ◽

Vol 149 (2) ◽

pp. 311-316 ◽

Cited By ~ 6

Author(s):

K. Bratke ◽

L. Krieghoff ◽

M. Kuepper ◽

W. Luttmann ◽

J. C. Virchow

Keyword(s):

T Cell ◽

Allergic Asthma ◽

T Cell Activation ◽

Cell Activation ◽

Cd8 T Cell ◽

Serological Status ◽

The Impact

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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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The Impact of DMARD and Anti-TNF Therapy on Functional Characterization of Short-Term T-Cell Activation in Patients with Rheumatoid Arthritis – A Follow-Up Study

PLoS ONE ◽

10.1371/journal.pone.0104298 ◽

2014 ◽

Vol 9 (8) ◽

pp. e104298 ◽

Cited By ~ 3

Author(s):

Balázs Szalay ◽

Áron Cseh ◽

Gergő Mészáros ◽

László Kovács ◽

Attila Balog ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Functional Characterization ◽

Short Term ◽

Follow Up Study ◽

The Impact

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Conditional Deletion of Pdcd1 Identifies the Cell-Intrinsic Action of PD-1 on Functional CD8 T Cell Subsets for Antitumor Efficacy

Frontiers in Immunology ◽

10.3389/fimmu.2021.752348 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sukanya Raghavan ◽

Nataliya Tovbis-Shifrin ◽

Christina Kochel ◽

Anandi Sawant ◽

Marielle Mello ◽

...

Keyword(s):

T Cell ◽

Tumor Growth ◽

Tumor Immunity ◽

T Cell Activation ◽

Cell Activation ◽

Cd8 T Cell ◽

T Cell Subsets ◽

Tamoxifen Treatment ◽

Phenotypic Analysis ◽

The Impact

Programmed cell death-1 (PD-1) blockade has a profound effect on the ability of the immune system to eliminate tumors, but many questions remain about the cell types involved and the underlying mechanisms of immune activation. To shed some light on this, the cellular and molecular events following inhibition of PD-1 signaling was investigated in the MC-38 colon carcinoma model using constitutive (PD-1 KO) and conditional (PD1cKO) mice and in wild-type mice treated with PD-1 antibody. The impact on both tumor growth and the development of tumor immunity was assessed. In the PD-1cKO mice, a complete deletion of Pdcd1 in tumor-infiltrating T cells (TILs) after tamoxifen treatment led to the inhibition of tumor growth of both small and large tumors. Extensive immune phenotypic analysis of the TILs by flow and mass cytometry identified 20-different T cell subsets of which specifically 5-CD8 positive ones expanded in all three models after PD-1 blockade. All five subsets expressed granzyme B and interferon gamma (IFNγ). Gene expression analysis of the tumor further supported the phenotypic analysis in both PD-1cKO- and PD-1 Ab-treated mice and showed an upregulation of pathways related to CD4 and CD8 T-cell activation, enhanced signaling through costimulatory molecules and IFNγ, and non-T-cell processes. Altogether, using PD-1cKO mice, we define the intrinsic nature of PD-1 suppression of CD8 T-cell responses in tumor immunity.

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