title: Signatures of protective memory immune responses during hepatitis C virus reinfection.
abstract: OBJECTIVE
  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.
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Abdel-Hakeem
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bédard
authors.affiliation: Institut National de Santé Publique du Québec, Laboratoire de Santé Publique du Québec (LSPQ), Sainte-Anne-de-Bellevue, Québec, Canada.
authors.forename: Donald
authors.initials: D
authors.lastname: Murphy
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de médecine familiale et de médecine d'urgence, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Bruneau
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de médecine, Université de Montréal, Montréal, Québec, Canada. Electronic address: naglaa.shoukry@umontreal.ca.
authors.forename: Naglaa H
authors.initials: NH
authors.lastname: Shoukry
mesh_terms: D000956:Antigens, Viral / Q000097:blood; D015415:Biomarkers / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D049109:Cell Proliferation; D018984:Epitopes, T-Lymphocyte / Q000097:blood; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006526:Hepatitis C / Q000097:blood / Q000175:diagnosis / Q000276:immunology* / Q000517:prevention & control; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D053699:Interleukin-7 Receptor alpha Subunit / Q000097:blood; D008213:Lymphocyte Activation; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000097:blood; D011792:Quebec; D012367:RNA, Viral / Q000097:blood; D055502:Secondary Prevention; D013997:Time Factors
chemical_list: D000956:Antigens, Viral; D015415:Biomarkers; D018984:Epitopes, T-Lymphocyte; D053699:Interleukin-7 Receptor alpha Subunit; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D012367:RNA, Viral
keywords: Cytokines; Immune Regulation; Protective Immunity; Viral Infection