ArticlePLoS pathogens2009
Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade.
Article in PLoS pathogens, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 207 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
207 citing papers in PubMed, 1 synthesis or guideline pooled it, 373 citations in OpenAlex.
- Safety and efficacy of immune checkpoint inhibitors in patients with HBV/HCV infection and advanced-stage cancer: A systematic review.Medicine · 2020Pooled it
- Recovery of hepatitis C specific T-cell responses after rituximab therapy in hepatitis C mixed cryoglobulinemic vasculitis.Journal of medical virology · 2018Trial
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- Trial
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- Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C.PLoS pathogens · 2013Trial
- Trial
- CD160 and PD-1 co-expression on HIV-specific CD8 T cells defines a subset with advanced dysfunction.PLoS pathogens · 2012Trial
- Trial
- Liver Macrophages in the Pathogenesis of Viral Hepatitis.Current issues in molecular biology · 2026Review
- T Cell Exhaustion in Cancer Immunotherapy: Heterogeneity, Mechanisms, and Therapeutic Opportunities.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- CD96 marks a phenotypically distinct checkpoint-associated HCV-specific CD8+ T-cell subset featuring memory-associated states.Frontiers in immunology · 2026Article
- Detection of anti-HCV antibodies in the clinical classification and epidemiological surveillance of HCV infection.Molecular biology reports · 2025Review
- The immune response of Boschveld chickens to a Newcastle disease vaccination program designed for commercial layers.Tropical animal health and production · 2025Article
- HBV-specific T-cell function is nonenhanced by tenofovir-induced decline in HBV viremia or HBsAg titer in chronic hepatitis B.Hepatology communications · 2025Article
- An immune-based predictive model for HBV clearance: validation in multicenter cohorts and mechanistic insights from in vivo studies.Virology journal · 2025Article
- Contrasting roles of PSGL-1 and PD-1 in regulating T-cell exhaustion and function during chronic viral infection.Journal of virology · 2025Article
- T Cell Exhaustion in Allergic Diseases and Allergen Immunotherapy: A Novel Biomarker?Current allergy and asthma reports · 2025Review
- Citrullinated peptides as drug candidates for rheumatoid arthritis.Frontiers in immunology · 2025Review
- Targeting archetypes of viral-driven cancers with immunotherapy: a perspective on immunogenicity within the tumor microenvironment.Frontiers in immunology · 2025Review
147 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors at 6 institutions in 2 countries.
Funding
Abstract
Viral persistence is associated with hierarchical antiviral CD8 T cell exhaustion with increased programmed death-1 (PD-1) expression. In HCV persistence, HCV-specific CD8 T cells from the liver (the site of viral replication) display increased PD-1 expression and a profound functional impairment that is not reversed by PD-1 blockade alone. Here, we report that the inhibitory receptor cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is preferentially upregulated in PD-1(+) T cells from the liver but not blood of chronically HCV-infected patients. PD-1/CTLA-4 co-expression in intrahepatic T cells was associated with a profound HCV-specific effector dysfunction that was synergistically reversed by combined PD-1/CTLA-4 blockade in vitro, but not by blocking PD-1 or CTLA-4 alone. A similar effect was observed in circulating HCV-specific CD8 T cells with increased PD-1/CTLA-4 co-expression during acute hepatitis C. The functional response to combined blockade was directly associated with CTLA-4 expression, lost with CD28-depletion and CD4-independent (including CD4(+)FoxP3(+) Tregs). We conclude that PD-1 and CTLA-4 pathways both contribute to virus-specific T cell exhaustion at the site of viral replication by a redundant mechanism that requires combined PD-1/CTLA-4 blockade to reverse. These findings provide new insights into the mechanisms of virus-specific T cell dysfunction, and suggest that the synergistic effect by combined inhibitory receptor blockade might have a therapeutic application against chronic viral infection in vivo, provided that it does not induce autoimmunity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.