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Abstract
Distinct molecular pathways govern the differentiation of CD8+ effector Tcells into memory or exhausted Tcells 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+ Tcells 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, Tcell differentiation, and the inflammatory response and correlated with subject age, sex, and the presence of HCV-specific CD4+ Tcell populations. These early changes in HCV-specific CD8+ Tcell transcription preceded the overt establishment of Tcell exhaustion, making this signature a prime target in the search for the regulatory origins of Tcell dysfunction in chronic viral infection.
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