Signatures of Protective Memory Immune Responses During Hepatitis C Virus Reinfection

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 147; no. 4; pp. 870 - 881.e8
• Main Authors: Abdel-Hakeem, Mohamed S., Bédard, Nathalie, Murphy, Donald, Bruneau, Julie, Shoukry, Naglaa H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2014
• Subjects: 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; Cytokines; Epitopes, T-Lymphocyte - blood; Gastroenterology and Hepatology; Hepacivirus - genetics; Hepacivirus - immunology; Hepatitis C - blood; Hepatitis C - diagnosis; Hepatitis C - immunology; Hepatitis C - prevention & control; Humans; Immune Regulation; Immunologic Memory; Immunophenotyping; Interleukin-7 Receptor alpha Subunit - blood; Lymphocyte Activation; Phenotype; Programmed Cell Death 1 Receptor - blood; Protective Immunity; Quebec; RNA, Viral - blood; Secondary Prevention; Time Factors; Viral Infection; Quebec; TNFα; Cytokines; Treg; ELISPOT; PBMC; IFN; SFC; HIV; Immune Regulation; ICS; Protective Immunity; HCV; IDUs; Viral Infection; regulatory T cell; interferon; enzyme-linked immunospot assay; intracellular cytokine staining; injection drug users; tumor necrosis factor alpha; hepatitis C virus; human immunodeficiency virus; peripheral blood mononuclear cell; spot-forming cell
• ISSN: 0016-5085; 1528-0012; 1528-0012
• DOI: 10.1053/j.gastro.2014.07.005

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. 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. 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 CD127hi 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 CD127neg, PD1lo 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. 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.