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Decrease of T-cells exhaustion markers programmed cell death-1 and T-cell immunoglobulin and mucin domain-containing
Sylwia Osuch1, Tomasz Laskus2, Hanna Berak3
1Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 3c Pawińskiego Street, 02-106, Warsaw, Poland.
Insights
Direct-acting antiviral treatment for hepatitis C virus (HCV) reverses immune exhaustion in T-cells. However, this immune recovery is limited in patients with advanced liver fibrosis.
Area of Science:
- Immunology
- Hepatology
- Virology
Background:
- Chronic hepatitis C virus (HCV) infection leads to functional exhaustion of CD4+ and CD8+ T-cells, characterized by increased programmed cell death-1 (PD-1) and T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) expression, and elevated interleukin-10 (IL-10) levels.
- This immune exhaustion impairs the host's ability to clear the virus and contributes to disease progression.
Purpose of the Study:
- To investigate the impact of direct-acting antiviral (DAA) treatment on T-cell exhaustion markers in patients with chronic hepatitis C.
- To determine if advanced liver fibrosis affects the reversal of immune exhaustion following DAA therapy.
Main Methods:
- Flow cytometry was used to measure frequencies of CD4+ and CD8+ T-cells expressing PD-1 and Tim-3 before and after DAA treatment in 76 HCV-positive patients and 18 controls.
- Enzyme-linked immunosorbent assay (ELISA) measured plasma IL-10 levels.
Main Results:
- HCV-positive patients exhibited higher frequencies of exhausted T-cells (CD4+PD-1+, CD4+PD-1+Tim-3+, CD8+PD-1+Tim-3+) and higher IL-10 levels compared to controls.
- DAA treatment significantly decreased frequencies of CD4+Tim-3+, CD8+Tim-3+, CD4+PD-1+Tim-3+, CD8+PD-1+Tim-3+ T-cells, and IL-10 levels, while increasing frequencies of non-exhausted T-cells (CD4+PD-1-Tim-3-, CD8+PD-1-Tim-3-).
- Patients with advanced liver fibrosis showed altered PD-1 and Tim-3 expression, and DAA treatment had minimal effect on their immune exhaustion markers. HCV-specific CD8+ T-cell frequency declined post-treatment without changes in PD-1/Tim-3 expression.
Conclusions:
- Successful DAA treatment reverses the immune exhaustion phenotype in chronic hepatitis C patients.
- The reversal of immune exhaustion is significantly impaired in patients with advanced liver fibrosis, suggesting a need for alternative therapeutic strategies in this subgroup.
Abstract:
During chronic hepatitis C virus (HCV) infection, both CD4+ and CD8+ T-cells become functionally exhausted, which is reflected by increased expression of programmed cell death-1 (PD-1) and T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), and elevated anti-inflammatory interleukin 10 (IL-10) plasma levels. We studied 76 DAA-treated HCV-positive patients and 18 non-infected controls. Flow cytometry measured pretreatment frequencies of CD4+PD-1+, CD4+PD-1+Tim-3+ and CD8+PD-1+Tim-3+ T-cells and IL-10 levels measured by ELISA were significantly higher and CD4+PD-1-Tim-3- and CD8+PD-1-Tim-3- T-cells were significantly lower in patients than in controls. Treatment resulted in significant decrease of CD4+Tim-3+, CD8+Tim-3+, CD4+PD-1+Tim-3+ and CD8+PD-1+Tim-3+ T-cell frequencies as well as IL-10 levels and increase in CD4+PD-1-Tim-3- and CD8+PD-1-Tim-3- T-cells. There were no significant changes in the frequencies of CD4+PD-1+ T-cells, while CD8+PD-1+ T-cells increased. Patients with advanced liver fibrosis had higher PD-1 and lower Tim-3 expression on CD4+T-cells and treatment had little or no effect on the exhaustion markers. HCV-specific CD8+T-cells frequency has declined significantly after treatment, but their PD-1 and Tim-3 expression did not change. Successful treatment of chronic hepatitis C with DAA is associated with reversal of immune exhaustion phenotype, but this effect is absent in patients with advanced liver fibrosis.
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