Memory-like HCV-specific CD8+ T cells retain a molecular scar after cure of chronic HCV infection

Nat Immunol. 2021 Feb;22(2):229-239. doi: 10.1038/s41590-020-00817-w. Epub 2021 Jan 4.


In chronic hepatitis C virus (HCV) infection, exhausted HCV-specific CD8+ T cells comprise memory-like and terminally exhausted subsets. However, little is known about the molecular profile and fate of these two subsets after the elimination of chronic antigen stimulation by direct-acting antiviral (DAA) therapy. Here, we report a progenitor-progeny relationship between memory-like and terminally exhausted HCV-specific CD8+ T cells via an intermediate subset. Single-cell transcriptomics implicated that memory-like cells are maintained and terminally exhausted cells are lost after DAA-mediated cure, resulting in a memory polarization of the overall HCV-specific CD8+ T cell response. However, an exhausted core signature of memory-like CD8+ T cells was still detectable, including, to a smaller extent, in HCV-specific CD8+ T cells targeting variant epitopes. These results identify a molecular signature of T cell exhaustion that is maintained as a chronic scar in HCV-specific CD8+ T cells even after the cessation of chronic antigen stimulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Viral / immunology
  • Antiviral Agents / therapeutic use
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / virology
  • Gene Expression Profiling
  • Gene Regulatory Networks
  • Hepacivirus / drug effects
  • Hepacivirus / immunology*
  • Hepatitis C, Chronic / drug therapy
  • Hepatitis C, Chronic / genetics
  • Hepatitis C, Chronic / immunology*
  • Hepatitis C, Chronic / virology
  • Host-Pathogen Interactions
  • Humans
  • Immunologic Memory / genetics*
  • Phenotype
  • Remission Induction
  • Single-Cell Analysis
  • Transcriptome*
  • Treatment Outcome


  • Antigens, Viral
  • Antiviral Agents