Department of Medicine and Surgery, University of Parma, Parma, Italy; Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
Department of Medicine and Surgery, University of Parma, Parma, Italy.
J Hepatol. 2023 Jul;79(1):50-60. doi: 10.1016/j.jhep.2023.02.035. Epub 2023 Mar 7.
BACKGROUND & AIMS: In chronic HBV infection, elevated reactive oxygen species levels derived from dysfunctional mitochondria can cause increased protein oxidation and DNA damage in exhausted virus-specific CD8 T cells. The aim of this study was to understand how these defects are mechanistically interconnected to further elucidate T cell exhaustion pathogenesis and, doing so, to devise novel T cell-based therapies.
DNA damage and repair mechanisms, including parylation, CD38 expression, and telomere length were studied in HBV-specific CD8 T cells from chronic HBV patients. Correction of intracellular signalling alterations and improvement of antiviral T cell functions by the NAD precursor nicotinamide mononucleotide and by CD38 inhibition was assessed.
Elevated DNA damage was associated with defective DNA repair processes, including NAD-dependent parylation, in HBV-specific CD8 cells of chronic HBV patients. NAD depletion was indicated by the overexpression of CD38, the major NAD consumer, and by the significant improvement of DNA repair mechanisms, and mitochondrial and proteostasis functions by NAD supplementation, which could also improve the HBV-specific antiviral CD8 T cell function.
Our study delineates a model of CD8 T cell exhaustion whereby multiple interconnected intracellular defects, including telomere shortening, are causally related to NAD depletion suggesting similarities between T cell exhaustion and cell senescence. Correction of these deregulated intracellular functions by NAD supplementation can also restore antiviral CD8 T cell activity and thus represents a promising potential therapeutic strategy for chronic HBV infection.
Correction of HBV-specific CD8 T cell dysfunction is believed to represent a rational strategy to cure chronic HBV infection, which however requires a deep understanding of HBV immune pathogenesis to identify the most important targets for functional T cell reconstitution strategies. This study identifies a central role played by NAD depletion in the intracellular vicious circle that maintains CD8 T cell exhaustion, showing that its replenishment can correct impaired intracellular mechanisms and reconstitute efficient antiviral CD8 T cell function, with implications for the design of novel immune anti-HBV therapies. As these intracellular defects are likely shared with other chronic virus infections where CD8 exhaustion can affect virus clearance, these results can likely also be of pathogenetic relevance for other infection models.
在慢性乙型肝炎病毒（HBV）感染中，功能失调的线粒体产生的高水平活性氧物质可导致耗尽的病毒特异性 CD8 T 细胞中蛋白质氧化和 DNA 损伤增加。本研究旨在深入了解这些缺陷的机制关联，以进一步阐明 T 细胞耗竭的发病机制，并在此基础上设计新型基于 T 细胞的治疗方法。
研究了慢性 HBV 患者的 HBV 特异性 CD8 T 细胞中的 DNA 损伤和修复机制，包括 PARylation、CD38 表达和端粒长度。评估了 NAD 前体烟酰胺单核苷酸和 CD38 抑制对纠正细胞内信号改变和改善抗病毒 T 细胞功能的作用。
HBV 特异性 CD8 细胞中 DNA 损伤的增加与包括 NAD 依赖性 PARylation 在内的缺陷性 DNA 修复过程有关，这在慢性 HBV 患者的 HBV 特异性 CD8 细胞中是如此。NAD 耗竭的标志是 CD38 的过度表达，CD38 是 NAD 的主要消耗者，而 NAD 的补充则显著改善了 DNA 修复机制以及线粒体和蛋白稳态功能，这也可以改善 HBV 特异性抗病毒 CD8 T 细胞功能。
我们的研究描绘了一个 CD8 T 细胞耗竭模型，其中包括端粒缩短在内的多种相互关联的细胞内缺陷与 NAD 耗竭有因果关系，这表明 T 细胞耗竭与细胞衰老之间存在相似性。通过 NAD 补充纠正这些失调的细胞内功能也可以恢复抗病毒 CD8 T 细胞的活性，因此代表了慢性 HBV 感染的一种有前途的潜在治疗策略。
纠正 HBV 特异性 CD8 T 细胞功能障碍被认为是治愈慢性 HBV 感染的合理策略，但需要深入了解 HBV 免疫发病机制，以确定功能 T 细胞重建策略的最重要靶点。本研究确定了 NAD 耗竭在维持 CD8 T 细胞耗竭的细胞内恶性循环中所起的核心作用，表明其补充可以纠正受损的细胞内机制，并重建有效的抗病毒 CD8 T 细胞功能，这对设计新型免疫抗 HBV 治疗具有重要意义。由于这些细胞内缺陷可能与其他可影响病毒清除的慢性病毒感染共享，因此这些结果也可能与其他感染模型的发病机制相关。
