Distinct molecular pathways govern the differentiation of CD8⁺ effector T cells into memory or exhausted T cells during acute and chronic viral infection, but these are not well studied in humans. Here, we employed an integrative systems immunology approach to identify transcriptional commonalities and differences between virus-specific CD8⁺ T cells from patients with persistent and spontaneously resolving hepatitis C virus (HCV) infection during the acute phase. We observed dysregulation of metabolic processes during early persistent infection that was linked to changes in expression of genes related to nucleosomal regulation of transcription, T cell differentiation, and the inflammatory response and correlated with subject age, sex, and the presence of HCV-specific CD4⁺ T cell populations. These early changes in HCV-specific CD8⁺ T cell transcription preceded the overt establishment of T cell exhaustion, making this signature a prime target in the search for the regulatory origins of T cell dysfunction in chronic viral infection.

^{在急性和慢性病毒感染期间，不同的分子途径控制着 CD8 +}效应 T 细胞分化为记忆或耗竭 T 细胞，但这些在人类中尚未得到充分研究。在这里，我们采用综合系统免疫学方法来识别急性期持续且自发消退的丙型肝炎病毒（HCV）感染患者的病毒特异性 CD8 ^{+ T 细胞之间的转录共性和差异。}我们观察到早期持续感染期间代谢过程的失调，这与核小体转录调节、T 细胞分化和炎症反应相关的基因表达变化有关，并与受试者年龄、性别和 HCV 特异性 CD4 的存在相关。⁺ T 细胞群。HCV 特异性 CD8 ⁺ T 细胞转录的这些早期变化先于 T 细胞耗竭的明显建立，使这一特征成为寻找慢性病毒感染中 T 细胞功能障碍的调节起源的主要目标。