C型肝炎は治療成功後も免疫細胞に “傷跡”を残す(Hepatitis C Leaves “Scars” in Immune Cells Even After Successful Treatment)

2024-07-10

2024-07-09 韓国基礎科学研究院(IBS)

韓国基礎科学研究所(IBS)のSHIN Eui-Cheolディレクター率いる研究チームは、慢性C型肝炎ウイルス(HCV)感染が免疫系に及ぼす長期的な影響を明らかにしました。治療後も「エピジェネティックスカー」が調節性T細胞に残り、炎症特性を持続することが判明しました。DAA治療でウイルスが消失した患者でも、活性化TREG細胞の頻度が高く、RNAシーケンシングとATAC-seq解析により、HCV患者のTREG細胞の転写およびエピジェネティックな風景がウイルス排除後も変化していることが示されました。この発見は、HCV治療後の患者の長期管理の重要性を示唆しており、持続的な免疫系の変化に対する新たな治療戦略の開発が必要とされています。

<関連情報>

直接作用型抗ウイルス薬によるC型慢性肝炎の治療成功後も、制御性T細胞のエピジェネティックな傷跡は残る Epigenetic scars in regulatory T cells are retained after successful treatment of chronic hepatitis C with direct-acting antivirals

So-Young Kim,June-Young Koh,Dong Hyeon Lee,Jun Yong Park,Won Kim,Eui-Cheol Shin
Journal of Hepatology Published:June 13, 2024
DOI:https://doi.org/10.1016/j.jhep.2024.06.011

Highlights

Increased T_REG in chronic HCV patients persists after DAA-induced viral clearance.
HCV clearance by DAA treatment does not abrogate inflammatory features of T_REG.
HCV clearance does not reverse inflammatory imprinting in the epigenome of T_REG.
Increased TNF⁺ T_REG in chronic HCV patients is maintained after viral clearance.

Abstract

Background & Aims
Chronic hepatitis C virus (HCV) infection results in abnormal immunological alterations, which are not fully normalized after viral elimination by direct-acting antiviral (DAA) treatment. Here we longitudinally examined phenotypic, transcriptomic, and epigenetic alterations in peripheral blood regulatory T (T_REG) cells from patients with chronic HCV infection according to DAA treatment.

Methods
Patients with chronic genotype 1b HCV infection who achieved sustained virologic response (SVR) by DAA treatment and age-matched healthy donors were recruited. Phenotypic characteristics of T_REG cells were investigated through flow cytometry analysis. Moreover, transcriptomic and epigenetic landscape of T_REG cells were analyzed using RNA-seq and ATAC-seq analysis.

Results
The T_REG cell population—especially the activated T_REG cell subpopulation—was expanded in peripheral blood during chronic HCV infection, and this expansion was sustained even after viral clearance. RNA-seq analysis revealed that viral clearance did not abrogate the inflammatory features of these T_REG cells, such as T_REG activation and TNF signal. Moreover, ATAC-seq analysis showed inflammatory imprinting in the epigenetic landscape of T_REG cells from patients, which remained after treatment. These findings were further confirmed by intracellular cytokine staining, demonstrating that T_REG cells exhibited inflammatory features and TNF production in chronic HCV infection that were maintained after viral clearance.

Conclusions
Overall, our results showed that during chronic HCV infection, the expanded T_REG cell population acquired inflammatory features at phenotypic, transcriptomic, and epigenetic levels, which were maintained even after successful viral elimination by DAA treatment. Further studies are warranted to examine the clinical significance of sustained inflammatory features in the T_REG cell population after recovery from chronic HCV infection.

Impact and implications
During chronic HCV infection, several immune components are altered both quantitatively and qualitatively. The recent introduction of DAAs led to a high cure rate of chronic HCV infection. Nevertheless, we have demonstrated that inflammatory features of T_REG cells are maintained at phenotypic, transcriptomic, and epigenetic levels even after successful DAA treatment. Further in-depth studies are required to investigate the long-term clinical outcomes of patients who have recovered from chronic HCV infection.