Abstract
Hepatitis C virus infection (HCV) represents a unique model to characterize, from early to late stages of infection, the T cell differentiation process leading to exhaustion of human CD8+ T cells. Here we show that in early HCV infection, exhaustion-committed virus-specific CD8+ T cells display a marked upregulation of transcription associated with impaired glycolytic and mitochondrial functions, that are linked to enhanced ataxia-telangiectasia mutated (ATM) and p53 signaling. After evolution to chronic infection, exhaustion of HCV-specific T cell responses is instead characterized by a broad gene downregulation associated with a wide metabolic and anti-viral function impairment, which can be rescued by histone methyltransferase inhibitors. These results have implications not only for treatment of HCV-positive patients not responding to last-generation antivirals, but also for other chronic pathologies associated with T cell dysfunction, including cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Disease
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Adolescent
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Adult
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Aged
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Antiviral Agents / pharmacology
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Antiviral Agents / therapeutic use
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Ataxia Telangiectasia Mutated Proteins / metabolism
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CD8-Positive T-Lymphocytes / immunology*
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Chronic Disease
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Epigenesis, Genetic / drug effects
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Gene Expression Profiling
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Gene Regulatory Networks / drug effects
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Glucose / metabolism
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Hepatitis C / blood
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Hepatitis C / genetics
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Hepatitis C / immunology*
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Hepatitis C / virology
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Histone Methyltransferases / metabolism*
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Humans
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology
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Middle Aged
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Mitochondria / drug effects
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Mitochondria / metabolism
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Principal Component Analysis
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Signal Transduction / drug effects
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Transcription, Genetic / drug effects
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Tumor Suppressor Protein p53 / metabolism*
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Young Adult
Substances
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Antiviral Agents
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Tumor Suppressor Protein p53
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Histone Methyltransferases
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Ataxia Telangiectasia Mutated Proteins
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Glucose