Heterologous T cell immunity in severe hepatitis C virus infection

Hepatitis C virus (HCV) can cause liver disease of variable severity. Expansion of preexisting memory CD8 T cells by cross-reactivity with a new heterologous virus infection has been shown in mice to shape the repertoire of the primary response and to influence virus-related immunopathology (Selin, L.K. 2004. Immunity. 20:5–16). To determine whether this mechanism can influence the course of HCV infection, we analyzed the features of the HCV-specific CD8 T cell response in eight patients with acute HCV infection, two of whom had a particularly severe illness. Patients with severe hepatitis, but not those with mild disease, showed an extremely vigorous CD8 T cell response narrowly focused on a single epitope (NS3 1073–1081), which cross-reacted with an influenza neuraminidase sequence. Our results suggest that CD8 T cell cross-reactivity influences the severity of the HCV-associated liver pathology and depicts a model of disease induction that may apply to different viral infections.

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HLA footprinting reveals a novel protective CD8 + T cell response in Hepatitis C virus infection

Journal of Infection ◽

10.1016/j.jinf.2009.10.009 ◽

2009 ◽

Vol 59 (6) ◽

pp. S428-S429 ◽

Cited By ~ 1

Author(s):

Karen Fitzmaurice ◽

Danijela Petrovic ◽

Silvana Gaudieri ◽

Elizabeth Freitas ◽

Stuart Sims ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Virus Infection ◽

Cell Response ◽

Cd8 T Cell ◽

T Cell Response ◽

Hepatitis C Virus Infection

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Escape from a Dominant HLA-B*15-Restricted CD8+ T Cell Response against Hepatitis C Virus Requires Compensatory Mutations outside the Epitope

Journal of Virology ◽

10.1128/jvi.05603-11 ◽

2011 ◽

Vol 86 (2) ◽

pp. 991-1000 ◽

Cited By ~ 15

Author(s):

M. Ruhl ◽

P. Chhatwal ◽

H. Strathmann ◽

T. Kuntzen ◽

D. Bankwitz ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Cell Response ◽

Cd8 T Cell ◽

T Cell Response ◽

Compensatory Mutations

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CD8+ T-Cell Response Promotes Evolution of Hepatitis C Virus Nonstructural Proteins

Gastroenterology ◽

10.1053/j.gastro.2011.02.060 ◽

2011 ◽

Vol 140 (7) ◽

pp. 2064-2073 ◽

Cited By ~ 35

Author(s):

Marianne Ruhl ◽

Torben Knuschke ◽

Kevin Schewior ◽

Lejla Glavinic ◽

Christoph Neumann-Haefelin ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Cell Response ◽

Cd8 T Cell ◽

T Cell Response ◽

Nonstructural Proteins

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Gamma-Chain Receptor Cytokines & PD-1 Manipulation to Restore HCV-Specific CD8+ T Cell Response during Chronic Hepatitis C

Cells ◽

10.3390/cells10030538 ◽

2021 ◽

Vol 10 (3) ◽

pp. 538

Author(s):

Julia Peña-Asensio ◽

Henar Calvo ◽

Miguel Torralba ◽

Joaquín Miquel ◽

Eduardo Sanz-de-Villalobos ◽

...

Keyword(s):

Hepatitis C ◽

T Cell ◽

Cell Response ◽

Cd8 T Cell ◽

Cell Receptor ◽

T Cell Response ◽

Hcv Infection ◽

Metabolic Reprogramming ◽

Gamma Chain ◽

Tcr Signalling

Hepatitis C virus (HCV)-specific CD8+ T cell response is essential in natural HCV infection control, but it becomes exhausted during persistent infection. Nowadays, chronic HCV infection can be resolved by direct acting anti-viral treatment, but there are still some non-responders that could benefit from CD8+ T cell response restoration. To become fully reactive, T cell needs the complete release of T cell receptor (TCR) signalling but, during exhaustion this is blocked by the PD-1 effect on CD28 triggering. The T cell pool sensitive to PD-1 modulation is the progenitor subset but not the terminally differentiated effector population. Nevertheless, the blockade of PD-1/PD-L1 checkpoint cannot be always enough to restore this pool. This is due to the HCV ability to impair other co-stimulatory mechanisms and metabolic pathways and to induce a pro-apoptotic state besides the TCR signalling impairment. In this sense, gamma-chain receptor cytokines involved in memory generation and maintenance, such as low-level IL-2, IL-7, IL-15, and IL-21, might carry out a positive effect on metabolic reprogramming, apoptosis blockade and restoration of co-stimulatory signalling. This review sheds light on the role of combinatory immunotherapeutic strategies to restore a reactive anti-HCV T cell response based on the mixture of PD-1 blocking plus IL-2/IL-7/IL-15/IL-21 treatment.

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CD8+T-Cell Response Against Hepatitis C Virus

Viral Immunology ◽

10.1089/088282402317340279 ◽

2002 ◽

Vol 15 (1) ◽

pp. 121-131 ◽

Cited By ~ 9

Author(s):

Xiao-Song He ◽

Harry B. Greenberg

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Cell Response ◽

Cd8 T Cell ◽

T Cell Response

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Comprehensive Analysis of CD8+-T-Cell Responses against Hepatitis C Virus Reveals Multiple Unpredicted Specificities

Journal of Virology ◽

10.1128/jvi.76.12.6104-6113.2002 ◽

2002 ◽

Vol 76 (12) ◽

pp. 6104-6113 ◽

Cited By ~ 140

Author(s):

Georg M. Lauer ◽

Kei Ouchi ◽

Raymond T. Chung ◽

Tam N. Nguyen ◽

Cheryl L. Day ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Cell Response ◽

Critical Role ◽

T Cell Responses ◽

Comprehensive Analysis ◽

T Cell Response ◽

Hcv Infection ◽

Cell Responses

ABSTRACT The hepatitis C virus (HCV)-specific CD8+-T-cell response is thought to play a critical role in HCV infection. Studies of these responses have largely relied on the analysis of a small number of previously described or predicted HCV epitopes, mostly restricted by HLA A2. In order to determine the actual breadth and magnitude of CD8+-T-cell responses in the context of diverse HLA class I alleles, we performed a comprehensive analysis of responses to all expressed HCV proteins. By using a panel of 301 overlapping peptides, we analyzed peripheral blood mononuclear cells (PBMC) from a cohort of 14 anti-HCV-positive, HLA A2-positive individuals in an enzyme-linked immunospot assay. Only four subjects had detectable HLA A2-restricted responses in PBMC, and only 3 of 19 predicted A2 epitopes were targeted, all of which were confirmed by tetramer analysis. In contrast, 9 of 14 persons showed responses with more comprehensive analyses, with many responses directed against previously unreported epitopes. These results indicate that circulating HCV-specific CD8+-T-cell responses can be detected in PBMC in the majority of infected persons and that these responses are heterogeneous with no immunodominant epitopes consistently recognized. Since responses to epitopes restricted by single HLA alleles such as HLA A2 do not predict the overall response in an individual, more comprehensive approaches, as shown here, should facilitate definition of the role of the CD8+-T-cell response in HCV infection. Moreover, the low level or absence of responses to many predicted epitopes provides a rationale for immunotherapeutic interventions to broaden cytotoxic-T-lymphocyte recognition.

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