Characterization of novel HLA-DR11-restricted HCV epitopes reveals both qualitative and quantitative differences in HCV-specific CD4+ T cell responses in chronically infected and non-viremic patients

Godkin, Andrew; Jeanguet, Nathalie; Thursz, Mark; Openshaw, Peter; Thomas, Howard

doi:10.1002/1521-4141(200105)31:5<1438::aid-immu1438>3.0.co;2-2

Cited by 58 publications

(51 citation statements)

References 31 publications

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“…Their importance has also been confirmed in the chimpanzee model [11,12]. Based on these observations, HCVspecific CD4 + T cell epitopes have been identified in infected patients [7,10,[13][14][15][16][17][18][19][20][21] with the final attempt to select peptides to be included in epitope-based vaccines or to be used for the development of tetramers. However, the identified sequences in NS3 and NS4 cover more than 60% of the proteins [21] and many of the HCV T cell epitopes were found to be specific to one patient only [7].…”

Section: Introductionmentioning

confidence: 82%

Differential capacity of T cell priming in naive donors of promiscuous CD4⁺ T cell epitopes of HCV NS3 and Core proteins

et al. 2007

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To understand the inter-individual and virus-independent variability of CD4 + T cell responses to HCV components, we evaluated the effect on these responses of HLA II molecules in uninfected healthy donors. Using HLA II-specific binding assays, we identified, in the Core and NS3 proteins, 21 long fragments and 24 15-mer peptides that bound to four to eight of the most preponderant HLA II molecules. We then evaluated the priming capacity of eight long promiscuous peptides in 12 HLA-unrelated healthy donors. The NS3 1250-1264 peptide primed T cells in all the naive donors, while five others were stimulating in at least half of the individuals. We also report sequences that bind to multiple HLA II molecules but are weakly immunogenic. We therefore conclude that (i) broad HLA II specificity is only a prerequisite for a peptide to be stimulating in multiple individuals, and (ii) promiscuous peptides widely differ in their capacity to prime CD4 + T cells from uninfected healthy donors. We suggest that these priming differences result from inter-individual variations in the peptide-specific T cell repertoire. Interestingly, five of the most immunogenic peptides we identified correspond to frequently targeted T cell epitopes in infected patients.

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Section: Introductionmentioning

confidence: 82%

Differential capacity of T cell priming in naive donors of promiscuous CD4⁺ T cell epitopes of HCV NS3 and Core proteins

et al. 2007

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“…During HCV infection, type 1 cytokine secretion patterns have been described for T cells involved in resolving infection [39,40], with possible participation of NKmediated activities [42], while predominant type 2 production has been described in chronic viremic infection [36,37]. We therefore studied cytokine production by peripheral NK cells freshly isolated from chronically infected patients.…”

Section: Production Of Il-10 and Conserved Ifn-c Production By Nk Celmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Additional suggestion of the involvement of innate immune mechanism(s) in the establishment of chronic HCV infection derive from the description of NK cell dysfunction (inhibition) following CD16-mediated triggering when CD81 molecules on NK cells are bound to HCV E2 protein [33]. In addition, reduced NK cell triggering mediated by reduced expression of NKG2D ligands (MIC-A and MIC-B) on mature DC (mDC) [34] as well as increased NK cell inhibition through increased CD94/NKG2A expression and TGF-b and IL-10 production [35,36,37] have been suggested to occur during HCV infection.Given the findings of relevant perturbations of NCR and of their involvement in the immune responses against chronic persistent infections including HIV and Mycobacterium tuberculosis [21][22][23][24][25][26][27][28] as well as the possible posttranscriptional regulation of NCR in the presence of increasing concentrations of TGF-b [38], we tried to determine whether HCV-infected patients show relevant modifications of triggering receptor expression and of NK cell functional derangement during the chronic phase of HCV infection. We report here on the analysis of freshly separated peripheral blood NK cells from HCV-infected patients, showing modified patterns of NCR expression and cytokine production.…”

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confidence: 99%

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Increased natural cytotoxicity receptor expression and relevant IL‐10 production in NK cells from chronically infected viremic HCV patients

et al. 2007

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Hepatitis C virus (HCV) readily establishes high-level lifelong persistent infection in the majority of immunocompetent adults with failure of HCV-specific CD8 + CTL to clear viral replication. Virus-induced conditioning of innate immune responses is a possible mechanism that may contribute to the impairment of virus-specific CD8 + CTL responses. Here, we analyzed whether triggering of NK cell receptor expression and function is affected during chronic viremic HCV infection. Flow cytometric analysis of purified resting peripheral NK cells showed no evidence of NK cell activation, while analysis of natural cytotoxicity receptors (NCR) showed that NK cells from HCVinfected patients had selective increased expression of NKp30 and NKp46. NK cells had corresponding conserved cytotoxic activity against all targets with the exception of HepG2 hepatoma cells. Freshly separated NK cells from HCV patients showed significant production of IL-10 and normal concentrations of IFN-c upon cell-mediated triggering. Thus, increased expression of NKp30 during HCV infection with increased IL-10 production could contribute, once NK cells localize in the liver, to a NK-DC crosstalk leading to skewing of subsequent adaptive immune responses and lack of virus control. IntroductionHepatitis C virus (HCV), a human hepatotropic Flaviviridae member not requiring insect vector transmission, may establish chronic replication and is responsible for a heavy burden of long-term disease including chronic hepatitis, cirrhosis, hepatocellular carcinoma, cryoglobulinaemia and vasculitis [1]. The high worldwide prevalence of infection (*170 million cases estimated by the World Health Organization) is associated, at least in part, to the chronic persistent course of infection that ensues in the majority of acutely infected patients (>85%) leading to continuous highlevel viral replication [2]. Both viral and host immune mechanisms contribute to the establishment of chronic infection. Spontaneous resolution of HCV infection has been linked to vigorous and multi-specific T cell responses, while attenuated CD4 + and CD8 + T cell responses have been observed during the chronic phase of viral persistence [3][4][5][6]. Failure to control HCV replication has also been associated with functional defects of virus-specific CD8 + cytotoxic T lymphocytes (CTL) [7][8][9][10] and, most recently, to the appearance of viral escape mutations in immunodominant CD8 + CTL epitopes associated with a lack of or relative defects in HCV-specific CD4 + T cell responses [11][12][13]. Adaptive immune defects during HCV infection are not limited to HCV-specific immune responses and may reflect the broader effects of HCV on the editing of T cell responses also on other antigen specificities [14].Perturbations of the innate immune system, including dendritic cell (DC) and natural killer (NK) cell function, are likely to contribute to the skewed finetuning of anti-HCV CD8 + and CD4 + T cell immune responses leading ultimately to T cell dysfunction [15,16]. Evidence supports an inv...

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“…9,10 Different methodical approaches, including proliferation assays using recombinant proteins or synthetic peptides, 9,10 ex vivo intracellular cytokine staining with peptides 89,90 and ex vivo multimer staining 91 demonstrated that spontaneous HCV clearance is associated Impact of the genetic restriction of virus-specific T-cell responses C Neumann-Haefelin and R Thimme with strong and multispecific CD4 þ T-cell responses, which are sustained after viral clearance. Most studies found that in acute resolving HCV infection, CD4 þ Tcell responses target mainly non-structural proteins, whereas in persistent HCV infection, CD4 þ T-cell responses to the core protein dominate.…”

Section: Role Of Class II Alleles In Hcv Infectionmentioning

confidence: 99%

Impact of the genetic restriction of virus-specific T-cell responses in hepatitis C virus infection

Thimme

2007

Genes Immun

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The immunobiology of hepatitis C virus (HCV) is significantly influenced by the host immune response to the virus, especially by virus-specific T-cell responses. Virus-specific T cells are restricted by human leucocyte antigen class I and II molecules. Of note, associations between these polymorphic loci and outcome and course of HCV infection have been reported in large and well-documented cohorts. This review will briefly summarize these studies and focus especially on the immunological and virological basis for the reported associations. The outcome and course of HCV infection is most likely determined by a complex interplay of genetic, immunological and virological factors. A better understanding of these host-virus interactions is essential not only to gain better insights into the mechanisms of viral clearance and persistence but also for the development of new antiviral vaccine strategies.

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Characterization of novel HLA-DR11-restricted HCV epitopes reveals both qualitative and quantitative differences in HCV-specific CD4+ T cell responses in chronically infected and non-viremic patients

Cited by 58 publications

References 31 publications

Differential capacity of T cell priming in naive donors of promiscuous CD4⁺ T cell epitopes of HCV NS3 and Core proteins

Differential capacity of T cell priming in naive donors of promiscuous CD4⁺ T cell epitopes of HCV NS3 and Core proteins

Increased natural cytotoxicity receptor expression and relevant IL‐10 production in NK cells from chronically infected viremic HCV patients

Impact of the genetic restriction of virus-specific T-cell responses in hepatitis C virus infection

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Characterization of novel HLA-DR11-restricted HCV epitopes reveals both qualitative and quantitative differences in HCV-specific CD4+ T cell responses in chronically infected and non-viremic patients

Cited by 58 publications

References 31 publications

Differential capacity of T cell priming in naive donors of promiscuous CD4+ T cell epitopes of HCV NS3 and Core proteins

Differential capacity of T cell priming in naive donors of promiscuous CD4+ T cell epitopes of HCV NS3 and Core proteins

Increased natural cytotoxicity receptor expression and relevant IL‐10 production in NK cells from chronically infected viremic HCV patients

Impact of the genetic restriction of virus-specific T-cell responses in hepatitis C virus infection

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Differential capacity of T cell priming in naive donors of promiscuous CD4⁺ T cell epitopes of HCV NS3 and Core proteins

Differential capacity of T cell priming in naive donors of promiscuous CD4⁺ T cell epitopes of HCV NS3 and Core proteins