Interrogating the Human CD8+ T Cell Response in HCV Infection
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Date
2014-03-20
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Johns Hopkins University
Abstract
Hepatitis C virus (HCV) infects nearly 170 million individuals worldwide and remains one of the leading causes of cirrhosis and hepatocellular carcinoma. Approximately 15-20% of individuals will spontaneously clear the infection, with the CD8+ T cell response crucial in achieving control. Given the highly diverse nature of HCV, the T cell response elicited by vaccines against HCV must achieve maximum cross reactivity against widely divergent circulating strains. We assessed T cell recognition of potential hepatitis C virus vaccine sequences generated using three rational approaches: 1) combining epitopes with predicted tight binding to the major histocompatibility complex (MHC), 2) consensus sequence (most common amino acid at each position), and 3) representative ancestral sequence that had been derived using Bayesian phylogenetic tools. No correlation was seen between peptide MHC binding affinity and frequency of recognition as measured by an interferon-gamma T cell response in human leukocyte antigen-matched HCV infected individuals. CD8+ T cells expanded with representative sequence HCV generally more broadly and robustly recognized highly diverse circulating HCV strains than T cell expanded with either consensus sequence or naturally occurring sequence variants. These data support the use of representative sequence in HCV vaccine design. In addition, we hypothesized that ongoing recognition of antigen with continued T cell receptor signaling is associated with upregulation of inhibitory T cell receptors. We characterized evolution of the CD8+ T cell response in the setting of absent, partial or incomplete, and complete recognition of antigen over time to determine if there is an association between prolonged antigenic stimulation and expression of inhibitory receptors. HCV-specific CD8+ T cell from HCV-infected subjects in a prospective longitudinal cohort were phenotyped for the activation markers HLA-DR and CD38; co-inhibitory receptors PD-1, TIM-3 and 2B4; and the memory molecule CD127 using polychromatic flow cytometry. The phenotype of these cells was compared in the setting of intact, mutated, and absent viral antigen within and across subjects. Our data point to the role of ongoing recognition of intact antigen in the T cell response to chronic viral infection
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HCV, hepatitis C virus, CD8 T cell, immunology, vaccine