Background & Aims

In immunosuppressed patients, persistent HEV infection is common and may lead to cirrhosis and liver failure. HEV clearance depends on an effective virus-specific CD8+ T-cell response; however, the knowledge gap around HEV-specific CD8+ T-cell epitopes has hindered analysis of the mechanisms of T-cell failure in persistent infection.

Methods

We comprehensively studied HEV-specific CD8+ T-cell responses in 46 patients with self-limiting (n = 34) or chronic HEV infection (n = 12), by epitope-specific expansion, functional testing, ex vivo peptide HLA class I tetramer multi-parametric staining, and viral sequence analysis.

Results

We identified 25 HEV-specific CD8+ T-cell epitopes restricted by 9 different HLA class I alleles. In self-limiting HEV infection, HEV-specific CD8+ T cells were vigorous, contracted after resolution of infection, and formed functional memory responses. In contrast, in chronic infection, the HEV-specific CD8+ T-cell response was diminished, declined over time, and displayed phenotypic features of exhaustion. However, improved proliferation of HEV-specific CD8+ T cells, increased interferon-γ production and evolution of a memory-like phenotype were observed upon reduction of immunosuppression and/or ribavirin treatment and were associated with viral clearance. In 1 patient, mutational viral escape in a targeted CD8+ T-cell epitope contributed to CD8+ T-cell failure.

Conclusion

Chronic HEV infection is associated with HEV-specific CD8+ T-cell exhaustion, indicating that T-cell exhaustion driven by persisting antigen recognition also occurs in severely immunosuppressed hosts. Functional reinvigoration of virus-specific T cells is at least partially possible when antigen is cleared. In a minority of patients, viral escape also contributes to HEV-specific CD8+ T-cell failure and thus needs to be considered in personalized immunotherapeutic approaches.

Lay summary

Hepatitis E virus (HEV) infection is usually cleared spontaneously (without treatment) in patients with fully functioning immune systems. In immunosuppressed patients, chronic HEV infection is common and can progress rapidly to cirrhosis and liver failure. Herein, we identified the presence of HEV-specific CD8+ T cells (a specific type of immune cell that can target HEV) in immunosuppressed patients, but we show that these cells do not function properly. This dysfunction appears to play a role in the development of chronic HEV infection in vulnerable patients.

中文翻译：

---

慢性戊型肝炎病毒感染中 CD8+ T 细胞衰竭的机制

背景与目标

在免疫抑制患者中，持续性 HEV 感染很常见，并可能导致肝硬化和肝功能衰竭。HEV 清除取决于有效的病毒特异性 CD8+ T 细胞反应；然而，围绕 HEV 特异性 CD8+ T 细胞表位的知识空白阻碍了对持续感染中 T 细胞衰竭机制的分析。

方法

我们通过表位特异性扩增、功能测试、离体肽 HLA I 类四聚体多聚体，全面研究了 46 名自限性（n = 34）或慢性 HEV 感染（n = 12）患者的 HEV 特异性 CD8+ T 细胞反应-参数染色和病毒序列分析。

结果

我们鉴定了 25 个 HEV 特异性 CD8+ T 细胞表位，这些表位受 9 个不同的 HLA I 类等位基因限制。在自限性 HEV 感染中，HEV 特异性 CD8+ T 细胞活力充沛，在感染消退后收缩，并形成功能性记忆反应。相比之下，在慢性感染中，HEV 特异性 CD8+ T 细胞反应减弱，随着时间的推移而下降，并表现出衰竭的表型特征。然而，在减少免疫抑制和/或利巴韦林治疗后观察到 HEV 特异性 CD8+ T 细胞的增殖改善、干扰素-γ 产生增加和记忆样表型的演变，并且与病毒清除有关。在 1 名患者中，靶向 CD8+ T 细胞表位中的突变病毒逃逸导致 CD8+ T 细胞衰竭。

结论

慢性 HEV 感染与 HEV 特异性 CD8+ T 细胞耗竭有关，这表明由持续抗原识别驱动的 T 细胞耗竭也发生在严重免疫抑制的宿主中。当抗原被清除时，病毒特异性 T 细胞的功能重振至少部分是可能的。在少数患者中，病毒逃逸也会导致 HEV 特异性 CD8+ T 细胞衰竭，因此需要在个性化免疫治疗方法中加以考虑。

总结

戊型肝炎病毒 (HEV) 感染通常在免疫系统功能齐全的患者中自发清除（无需治疗）。在免疫抑制患者中，慢性 HEV 感染很常见，可迅速发展为肝硬化和肝功能衰竭。在这里，我们确定了免疫抑制患者中存在 HEV 特异性 CD8+ T 细胞（一种可以靶向 HEV 的特定类型的免疫细胞），但我们发现这些细胞不能正常工作。这种功能障碍似乎在易感患者慢性 HEV 感染的发展中发挥作用。