Comprehensive analyses of CD8+ T cell responses during longitudinal study of acute human hepatitis C

Cox, Andrea L.; Mosbruger, Timothy; Lauer, Georg M.; Pardoll, Drew M.; Thomas, David L.; Ray, Stuart C.

doi:10.1002/hep.20749

Cited by 217 publications

(237 citation statements)

References 55 publications

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“…[1][2][3][4][5][6][7][8][9] In contrast, chronic infection is characterized by less vigorous and narrowly focused CD4 and CD8 T cell responses. The mechanisms responsible for immune failure in patients who do not succeed in clearing the virus spontaneously are still unclear.…”

Section: S Pontaneous Clearance Of Hepatitis C Virus Infectionmentioning

confidence: 99%

“…Most recent reports used wide panels of 10-to 15-mer HCV peptides that cannot distinguish the relative contribution of CD4 and CD8 cells to the overall antiviral T cell response. [5][6][7][8][9][10][11] Alternatively, a small number of preselected epitopes of known HLA restriction or whole recombinant HCV proteins were tested. [12][13][14][15][16][17][18] Moreover, only limited information is available about the ex vivo profile of cytokine production in the acute phase of infection, because ELISPOT and intracellular cytokine staining (ICS) analysis were based on the measure of interferon-␥ (IFN-␥) only.…”

Section: S Pontaneous Clearance Of Hepatitis C Virus Infectionmentioning

confidence: 99%

“…To address this issue, we analyzed the breadth, vigor, and quality of CD4 and CD8 responses simultaneously with panels of peptides covering the entire HCV sequence or containing the HLA-A2-binding motif, and with recombinant HCV proteins in 16 patients with acute HCV infection by tetramer staining, ELISPOT, and intracellular cytokine staining for interferon ␥, interleukin ( S pontaneous clearance of hepatitis C virus infection occurs in a small percentage of acutely infected patients and is associated with a vigorous cellular immune response of a broad specificity. [1][2][3][4][5][6][7][8][9] In contrast, chronic infection is characterized by less vigorous and narrowly focused CD4 and CD8 T cell responses. The mechanisms responsible for immune failure in patients who do not succeed in clearing the virus spontaneously are still unclear.…”

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confidence: 99%

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Outcome of acute hepatitis C is related to virus-specific CD4 function and maturation of antiviral memory CD8 responses

et al. 2006

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A timely, efficient, and coordinated activation of both CD4 and CD8 T cell subsets following HCV infection is believed to be essential for HCV control. However, to what extent a failure of the individual T cell subsets can contribute to the high propensity of HCV to persist is still largely undefined. To address this issue, we analyzed the breadth, vigor, and quality of CD4 and CD8 responses simultaneously with panels of peptides covering the entire HCV sequence or containing the HLA-A2-binding motif, and with recombinant HCV proteins in 16 patients with acute HCV infection by tetramer staining, ELISPOT, and intracellular cytokine staining for interferon ␥, interleukin ( S pontaneous clearance of hepatitis C virus infection occurs in a small percentage of acutely infected patients and is associated with a vigorous cellular immune response of a broad specificity. [1][2][3][4][5][6][7][8][9] In contrast, chronic infection is characterized by less vigorous and narrowly focused CD4 and CD8 T cell responses. The mechanisms responsible for immune failure in patients who do not succeed in clearing the virus spontaneously are still unclear. Although there have been several reports of the hepatitis C virus (HCV)-specific cellular immune response during acute illness, a comprehensive study analyzing simultaneously the contribution of each T cell subsets to the mechanisms of clearance or persistence has never been performed. Most recent reports used wide panels of 10-to 15-mer HCV peptides that cannot distinguish the relative contribution of CD4 and CD8 cells to the overall antiviral T cell response. [5][6][7][8][9][10][11] Alternatively, a small number of preselected epitopes of known HLA restriction or whole recombinant HCV proteins were tested. [12][13][14][15][16][17][18] Moreover, only limited information is available about the ex vivo profile of cytokine production in the acute phase of infection, because ELISPOT and intracellular cytokine staining (ICS) analysis were based on the measure of interferon-␥ (IFN-␥) only. 12,19 In the present study, we used panels of genotypematched, overlapping peptides covering the entire HCV sequence to obtain a reliable representation of the overall T cell response to HCV, associated with control of infec-

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Section: S Pontaneous Clearance Of Hepatitis C Virus Infectionmentioning

confidence: 99%

Section: S Pontaneous Clearance Of Hepatitis C Virus Infectionmentioning

confidence: 99%

mentioning

confidence: 99%

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Outcome of acute hepatitis C is related to virus-specific CD4 function and maturation of antiviral memory CD8 responses

et al. 2006

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“…The mechanism on account of which the immune response fails to control the virus remains, however, unclear. Because, the identification of acute HCV infection is rare, only in a limited number of persons a longitudinal follow-up of HCV-specific T-cell responses from the early phase of HCV infection has been reported [6,9,[11][12][13]. Most of these responses have been studied using a limited number of epitopes, mostly restricted to the HLA A2 haplotype [7,9,14,15].…”

Section: Introductionmentioning

confidence: 99%

HCV‐specific T‐cell responses in injecting drug users: evidence for previous exposure to HCV and a role for CD4+ T cells focussing on nonstructural proteins in viral clearance

Ruys

Nanlohy

Berg

et al. 2008

Journal of Viral Hepatitis

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SUMMARY. In order to understand the parameters associated with resolved hepatitis C virus (HCV)-infection, we analysed the HCV-specific T-cell responses longitudinally in 13 injecting drug-users (IDUs) with a prospectively identified acute HCV infection. Seven IDUs cleared HCV and six IDUs remained chronically infected. T-cell responses were followed in the period needed to resolve and a comparable time span in chronic carriers. Ex vivo T-cell responses were measured using interferon-c Elispot assays after stimulation with overlapping peptide pools spanning the complete HCV genome. CD4+ memory-T-cell responses were determined after 12-day stimulation with HCV proteins. The maximum response was compared between individuals. The T-cell responses measured directly ex vivo were weak but significantly higher in resolvers compared to chronic carriers, whereas the CD4+ memory-T-cell response was not different between resolvers and chronic carriers. However, HCV Core protein was targeted more often in chronic carriers compared to individuals resolving HCV infection. CD4+ T-cell responses predominantly targeting nonstructural proteins were associated with resolved HCV infection. Interestingly, observation of memory-T-cell responses present before the documented HCV-seroconversion suggests that reinfections in IDUs occur often. The presence of these responses however, were not predictive for the outcome of infection. However, a transition of the HCV-specific CD4+ memory-Tcell response from targeting Core to targeting nonstructural proteins during onset of infection was associated with a favourable outcome. Therefore, the specificity of the CD4+ memory-T-cell responses measured after 12-day expansion seems most predictive of resolved infection.

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“…By contrast, patients with chronic hepatitis C tend to have late, transient, and/or narrowly focused T cell responses (9,10). Failure to sustain virus-specific CD8 + lymphocytes is frequently observed in the chronically infected patients, and T cells from these patients are associated with features such as functional exhaustion as well as tolerance induction and developmental arrest (11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

TCR-Redirected Human T Cells Inhibit Hepatitis C Virus Replication: Hepatotoxic Potential Is Linked to Antigen Specificity and Functional Avidity

Pasetto

Frelin

Aleman

et al. 2012

The Journal of Immunology

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Virus-specific CTL with high levels of functional avidity have been associated with viral clearance in hepatitis C virus (HCV) infection and with enhanced protective immunity. In chronic HCV infection, lack of antiviral CTL is frequently observed. In this study, we aim to investigate novel HCV TCRs that differ in Ag specificity. This involved isolating new HCV-specific murine TCRs that recognize a conserved HLA-A2–restricted CTL epitope within the nonstructural protein (NS) 5A viral protein and comparing them with TCRs recognizing another conserved CTL target in the NS3 viral protein. This was done by expressing the TCRs in human T cells and analyzing the function of the resulting TCR-transduced T cells. Our result indicates that these TCRs are efficiently assembled in transduced human T cells. They recognize peptide-loaded targets and demonstrate polyfunctional features such as IL-2, IFN-γ, and TNF-α secretion. However, in contrast to NS3-specific TCRs, the NS5A TCR-transduced T cells consist of a smaller proportion of polyfunctional T cells and require more peptide ligands to trigger the effector functions, including degranulation. Despite the differences, NS5A TCRs show effective inhibition of HCV replication in human hepatoma cells with persistent HCV RNA replication. Moreover, cellular injury demonstrated by aspartate aminotransferase release and cell death is less significant in the hepatoma cells following coincubation with NS5A TCR-transduced T cells, which is a property consistent with noncytotoxic antiviral CTLs. Our results suggest that HCV TCR-transduced T cells may be promising for the treatment of patients with chronic HCV infections.

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Comprehensive analyses of CD8+ T cell responses during longitudinal study of acute human hepatitis C

Cited by 217 publications

References 55 publications

Outcome of acute hepatitis C is related to virus-specific CD4 function and maturation of antiviral memory CD8 responses

Outcome of acute hepatitis C is related to virus-specific CD4 function and maturation of antiviral memory CD8 responses

HCV‐specific T‐cell responses in injecting drug users: evidence for previous exposure to HCV and a role for CD4+ T cells focussing on nonstructural proteins in viral clearance

TCR-Redirected Human T Cells Inhibit Hepatitis C Virus Replication: Hepatotoxic Potential Is Linked to Antigen Specificity and Functional Avidity

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