Signatures of protective memory immune responses during hepatitis C virus reinfection

Gastroenterology. 2014 Oct;147(4):870-881.e8. doi: 10.1053/j.gastro.2014.07.005. Epub 2014 Jul 16.


Background & aims: Development of a vaccine against hepatitis C virus (HCV) has been hindered by our limited understanding of immune correlates of protection during real-life exposure to the virus. We studied the immune response during HCV reinfection.

Methods: We analyzed blood samples from participants in the Montreal Acute Hepatitis C Injection Drug User Cohort Study who were reinfected with HCV from 2009 to 2012. Five patients spontaneously resolved their second infection and 4 developed chronic infections. We monitored the phenotypic and functional dynamics of HCV-specific memory T cell responses in all subjects during natural re-exposure and re-infection.

Results: Populations of CD4(+) and CD8(+) T cells with HCV-specific polyfunctional memory were expanded in all 5 individuals who resolved 2 successive HCV infections. We detected CD127(hi) HCV-specific memory CD8(+) T cells before reinfection regardless of a subject's ability to clear subsequent infections. Protection against viral persistence was associated with the expansion of a CD127(neg), PD1(lo) effector memory T cells at the peak of the response. We also observed broadening of T-cell response, indicating generation of de novo T-cell responses. The 4 individuals who failed to clear their subsequent infection had limited expansion of HCV-specific CD4(+) and CD8(+) memory T cells and expressed variable levels of the exhaustion marker PD1 on HCV-specific CD8(+) T cells. Dominant epitope regions of HCV strains isolated from patients with persistent reinfection had sequence variations that were not recognized by the pre-existing memory T cells.

Conclusions: Protection from persistent HCV reinfection depends on the magnitude, breadth, and quality of the HCV-specific memory T-cell response. Sequence homology among viruses and ability of T cells to recognize multiple strains of HCV are critical determinants of protective memory.

Keywords: Cytokines; Immune Regulation; Protective Immunity; Viral Infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Viral / blood
  • Biomarkers / blood
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / virology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / virology
  • Cell Proliferation
  • Epitopes, T-Lymphocyte / blood
  • Hepacivirus / genetics
  • Hepacivirus / immunology*
  • Hepatitis C / blood
  • Hepatitis C / diagnosis
  • Hepatitis C / immunology*
  • Hepatitis C / prevention & control
  • Humans
  • Immunologic Memory*
  • Immunophenotyping
  • Interleukin-7 Receptor alpha Subunit / blood
  • Lymphocyte Activation
  • Phenotype
  • Programmed Cell Death 1 Receptor / blood
  • Quebec
  • RNA, Viral / blood
  • Secondary Prevention
  • Time Factors


  • Antigens, Viral
  • Biomarkers
  • Epitopes, T-Lymphocyte
  • Interleukin-7 Receptor alpha Subunit
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • RNA, Viral