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Programmed cell death-1 is involved with peripheral blood immune cell profiles in patients with hepatitis C virus
Miyabi Miura1, Michiko Nishino1, Kazunori Kawaguchi1
1Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan.
Abstract:
Mutations in the non-structural protein regions of hepatitis C virus (HCV) are a cause of a non-sustained virological response (SVR) to treatment with direct-acting antivirals (DAAs) for chronic hepatitis; however, there are non-SVR cases without these mutations. In this study, we examined immune cell profiles in peripheral blood before and after ombitasvir/paritaprevir/ritonavir treatment and screened for genes that could be used to predict the therapeutic effects of DAAs. Fluorescence-activated cell sorting analysis indicated that the median frequencies of programmed cell death-1-positive (PD-1+) effector regulatory T cells (eTregs), PD-1+CD8+ T cells, and PD-1+Helper T cells were decreased significantly in SVR cases, but without significant changes in non-SVR cases. The frequency of PD-1+ naïve Tregs was significantly higher in the SVR group than in the non-SVR group before and after treatment. Similar results were found in patients treated with other DAAs (e.g., daclatasvir plus asunaprevir) and supported an immune response after HCV therapy. RNA-sequencing analysis indicated a significant increase in the expression of genes associated with the immune response in the SVR group, while genes related to intracellular and extracellular signal transduction were highly expressed in the non-SVR group. Therefore, we searched for genes associated with PD-1+ eTregs and CD8+ T cells that were significantly different between the SVR and non-SVR groups and found that T-box transcription factor 21 was associated with the non-SVR state. These results indicate that PD-1-related signaling pathways are associated with a non-SVR mechanism after DAAs treatment separate from mutation-related drug resistance.
Insights
Hepatitis C virus (HCV) treatment response can be predicted by immune cell changes, not just mutations. Programmed cell death-1 (PD-1) related pathways and T-cell profiles offer insights into treatment outcomes for direct-acting antivirals (DAAs).
Area of Science:
- Immunology
- Virology
- Genetics
Background:
- Mutations in hepatitis C virus (HCV) non-structural proteins are linked to non-sustained virological response (SVR) to direct-acting antivirals (DAAs).
- However, some patients do not achieve SVR even without these specific mutations, suggesting alternative mechanisms for treatment failure.
Purpose of the Study:
- To investigate immune cell profiles and gene expression changes in patients undergoing DAA treatment for chronic hepatitis C.
- To identify biomarkers that predict therapeutic effects and understand non-SVR mechanisms beyond drug resistance mutations.
Main Methods:
- Fluorescence-activated cell sorting (FACS) was used to analyze peripheral blood immune cell frequencies (PD-1+ T cells) before and after DAA treatment.
- RNA sequencing was performed to compare gene expression patterns between patients who achieved SVR and those who did not.
- Correlations between immune cell profiles, gene expression, and treatment outcomes were assessed.
Main Results:
- A significant decrease in PD-1+ effector regulatory T cells (eTregs), PD-1+CD8+ T cells, and PD-1+Helper T cells was observed in SVR cases, but not in non-SVR cases.
- Higher frequencies of PD-1+ naïve Tregs were found in the SVR group compared to the non-SVR group, both pre- and post-treatment.
- RNA-seq revealed increased immune response genes in the SVR group and enhanced signal transduction genes in the non-SVR group. T-box transcription factor 21 was associated with the non-SVR state.
Conclusions:
- PD-1-related signaling pathways play a role in non-SVR mechanisms following DAA treatment, independent of mutation-related drug resistance.
- Immune cell profiling, particularly PD-1+ T cell subsets, can serve as a predictive marker for DAA treatment efficacy in chronic hepatitis C.
- Gene expression analysis further supports distinct immune and signaling profiles associated with treatment response or failure.
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