Early Transcriptional Divergence Marks Virus-Specific Primary Human CD8+ T Cells in Chronic versus Acute Infection

Abstract

Summary 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 were 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.

Role of soluble inflammatory mediators and different immune cell populations in early control of symptomatic acute hepatitis C virus infection

“…Correlation analysis further revealed a distinct pattern in SC patients, which differed clearly from that observed in NC patients, suggesting a dysregulated SIM production in patients not being able to control the infection. Similar dysregulation of immune cell and metabolic features of HCV‐specific CD8 + T cells were recently described in acute HCV . Further, baseline viral load correlated with the expression of four SIMs in SC patients only, but none in NC patients.…”

“…In detail, CD4 + T cells were more activated and CD56 dim NK cells were increased. This is in line with a recent report, where a decline in HCV‐specific CD4 + T cell counts was apparent in aHCV patients evolving to chronic infection . Hence, we hypothesize that activated NK cells might contribute to deletion of activated CD4 + T cells, a regulatory feature of NK cells described previously during viral infection in mice .…”

“…This is in line with a recent report, where a decline in HCV-specific CD4 + T cell counts was apparent in aHCV patients evolving to chronic infection. 22 Hence, we hypothesize that activated NK cells might contribute to deletion of activated CD4 + T cells, a regulatory feature of NK cells described previously during viral infection in mice. 21,23 This loss of "beneficial" CD4 + T cells may be the reason for viral persistence in NC patients.…”

Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection

“…14c) 23 and in HCV (early chronicallyevolving patients) infections ( Supplementary Fig. 14d) 26 . This suggests that the HMTs/p53 inhibitors might also be effective in other viral and non-viral chronic pathologies (including cancer) sharing a T cell exhaustion phenotype.…”

“…In the LCMV mouse model of chronic infection, glycolysis downregulation and OXPHOS impairment are hallmarks of exhaustion and are more evident in the PD1 hi than in the PD1 int subset of exhausted CD8+ T cells 25 . A dysregulated gene expression profile consistent with these metabolic changes has recently been described in human HCVspecific CD8+ T cells committed to exhaustion 26 , but a functional assessment of the actual contribution of metabolic and epigenetic state alteration to CD8+ T cell dysfunction and its causal association with exhaustion is still lacking 27 .…”