Comprehensive Determinant Mapping of the Hepatitis C-Specific CD8 Cell Repertoire Reveals Unpredicted Immune Hierarchy

Anthony, Donald D.; Valdez, Hernán; Post, Anthony B.; Carlson, Nicole L.; Heeger, Peter S.; Lehmann, Paul

doi:10.1006/clim.2001.5193

Cited by 24 publications

(21 citation statements)

References 48 publications

(34 reference statements)

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“…On the whole, 13 pools were immunogenic in greater than 50% of recovered subjects, defining 8 discrete, highly immunogenic regions that may be useful in vaccine design, in Core (pools 2-3), NS3 (pools 4, 7, and 10-12), NS4 (pools [16][17], NS5A (pools [19][20], and NS5B (pools 29 and 34). Interestingly, the similar antigenic repertoire between the recovered and chronic subjects (particularly the CD8 T-cell response) suggested that HCV persistence is not due to a differential antigenic hierarchy but rather a global HCVspecific T-cell suppression.…”

Section: Discussionmentioning

confidence: 99%

“…For example, since CD8 T cells are class I human leukocyte antigen (HLA)-restricted, many studies of HCV-specific CD8 T cells used preselected peptides with classic binding motifs for highly prevalent HLA types (e.g., HLA-A2). 6,9,11,16 By contrast, T-cell epitopes may lack these classical motifs 14,17,18 while certain mutable viruses may even adapt to the more common or conserved HLA alleles, making it problematic to focus on only highly prevalent HLA types. 19 Furthermore, prolonged in vitro stimulation used to expand T cells in earlier studies may be biased towards T cells that survive the culture conditions and underestimate the true virus-spe-cific T-cell frequency.…”

Section: H Epatitis C Virus (Hcv) Is a Hepatotropic Virusmentioning

confidence: 99%

“…14,17,18,25 We adopted this approach to comprehensively examine the circulating HCV-specific T-cell response relative to outcome, using a peptide library spanning the entire HCV core, NS3-NS5 regions. Our results suggest significant differences in HCV-specific Tcell frequency and scope between HCV clearance and persistence, particularly for the CD4 T-cell subset.…”

Section: H Epatitis C Virus (Hcv) Is a Hepatotropic Virusmentioning

confidence: 99%

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Suppression of HCV-specific T cells without differential hierarchy demonstrated in persistent HCV infection

et al. 2003

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Hepatitis C virus (HCV) has a high propensity for persistence. To better define the immunologic determinants of HCV clearance and persistence, we examined the circulating HCVspecific T-cell frequency, repertoire, and cytokine phenotype ex vivo in 24 HCV seropositive subjects (12 chronic, 12 recovered), using 361 overlapping peptides in 36 antigenic pools that span the entire HCV core, NS3-NS5. Consistent with T-cell-mediated control of HCV, the overall HCV-specific type-1 T-cell response was significantly greater in average frequency (0.24% vs. 0.04% circulating lymphocytes, P ‫؍‬ .001) and scope (14/36 vs. 4/36 pools, P ‫؍‬ .002) among the recovered than the chronic subjects, and the T-cell response correlated inversely with HCV titer among the chronic subjects (R ‫؍‬ ؊0.51, P ‫؍‬ .049). Although highly antigenic regions were identified throughout the HCV genome, there was no apparent difference in the overall HCV-specific T-cell repertoire or type-1/type-2 cytokine profile relative to outcome. Notably, HCV persistence was associated with a reversible CD4-mediated suppression of HCV-specific CD8 T cells and with higher frequency of CD4 ؉ CD25 ؉ regulatory T cells (7.3% chronic vs. 2.5% recovered, P ‫؍‬ .002) that could directly suppress HCV-specific type-1 CD8 T cells ex vivo. In conclusion, we found that HCV persistence is associated with a global quantitative and functional suppression of HCV-specific T cells but not differential antigenic hierarchy or cytokine phenotype relative to HCV clearance. The high frequency of CD4 ؉ CD25 ؉ regulatory T cells and their suppression of HCV-specific CD8 T cells ex vivo suggests a novel role for regulatory T cells in HCV persistence.

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Section: Discussionmentioning

confidence: 99%

Section: H Epatitis C Virus (Hcv) Is a Hepatotropic Virusmentioning

confidence: 99%

Section: H Epatitis C Virus (Hcv) Is a Hepatotropic Virusmentioning

confidence: 99%

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Suppression of HCV-specific T cells without differential hierarchy demonstrated in persistent HCV infection

et al. 2003

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“…51,52 The possibility that this quantitative difference reflects the use of tetramers able to detect CD8 ϩ T cells restricted to selected human leukocyte antigen class I molecules cannot be excluded totally, 53 but recent analysis performed using broad peptide libraries did not detect higher HCV-specific CD8 ϩ T-cell frequencies. 53,54 In addition, quantitative defects are not limited to the cellular arm of the adaptive response because antibody production of limited quantity and restricted to the immunoglobulin G1 isotype has been reported in acute HCV infections. 37 Several factors likely are responsible for these defects of the adaptive immunity, including intrahepatic recruitment and subsequent deletion of activated virus-specific CD8 ϩ T cells, 55 antigendriven T-or B-cell exhaustion, 56 the ability of liver sinusoidal endothelial cells to suppress the expansion of T-helper 1-type cells, 57 and the production of viral proteins with immunomodulatory effects.…”

Section: Profiles Of Adaptive Immune Responses Early After Hbv and Hcmentioning

confidence: 99%

Kinetics of the immune response during HBV and HCV infection

2003

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The innate immune system has a role not only in protecting the host during the initial period of virus infection, but also in shaping the nature of the adaptive immune response. In this review, we follow the kinetics of the virologic and immunologic events occurring from the time of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. We primarily discuss how the early events after infection might influence the development of the adaptive immune response in these 2 important viral infections and how new strategies for more efficient preventive and therapeutic vaccines can be derived from this knowledge. (HEPATOLOGY 2003; 38:4-13.)H epatitis B (HBV) and hepatitis C (HCV) viruses are the 2 major causes of chronic liver inflammation worldwide. 1,2 Despite distinct virologic features, both viruses are preferentially hepatotropic, not directly cytopathic, and elicit liver diseases that share several aspects of their natural history. HBV and HCV infections share also some important features of the adaptive immune response. Multispecific antiviral CD4 and CD8 responses with a T-helper type 1 profile of cytokine production are detectable in the blood of subjects with a self-limited infection. [3][4][5][6][7][8][9][10][11][12][13][14][15][16] These responses are stronger than those found in patients with chronic infection. [17][18][19][20][21] Based on these observations, it has been proposed that the ability to mount an efficient cellular immune response is the main mechanism responsible for HBV and HCV control, whereas a defect in this response leads to chronicity. 2,22 However, the lack of suitable animal models to study the pathogenesis of HBV and HCV infections has so far hampered a definitive demonstration that associations between different infection outcomes and different vigor and breadth of T-cell responses have a causative effect. A recent report in HCV-infected chimpanzees, in which a clear association between T-cell response and virus clearance was not found, 23 added a further note of caution. Even so, it is difficult to argue against the importance of the cellular immune response in HBV and HCV control. In chimpanzees infected with HCV, expansion of a multispecific and sustained HCV-specific CD8 ϩ T-cell-mediated response was observed in 2 of 2 animals that cleared the virus, but not in the 4 animals that developed a chronic infection. 24 These results have been confirmed by recent reports showing that expansion of interferon ␥ (IFN-␥) ϩ , CD8 ϩ , and CD4 ϩ T cells precedes viral clearance in patients studied during the incubation phase of acute HCV infection in man 10 and in HCV-infected chimpanzees. 25 Similar findings have been reported in animal models of HBV infection 26 and in patients studied during the incubation phase of HBV infection, 27 in whom reduced early expansion of virusspecific T cells was associated with virus persistence. Moreover, the importance of virus-specific CD8 ϩ T cells in HBV control has been confirmed further by CD8 ϩ T-cell deletion experiments performed in HBV-i...

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“…Translating these notions into immune diagnostic considerations one might predict that high clonal sizes and the expression of activation/effector molecules would distinguish between CD8 + cells that are actively engaged in an immune response vs. resting memory cells. The clonal size, however, is not a reliable indicator of active immune processes --frequencies of virus-specific CD8 + cells are frequently low in chronic viral infections [14][15][16]. When antigen persists, the antigenspecific CD8 + cell population undergoes exhaustion and the frequencies of the antigen-specific cells drop to barely detectable numbers as is typically seen in the chronic phase of many infections, including HIV, hepatitis B and C or tuberculosis [14,17,18].…”

Section: Introductionmentioning

confidence: 99%

Granzyme B production distinguishes recently activated CD8+ memory cells from resting memory cells

Nowacki

Küerten

Zhang³

et al. 2007

Cellular Immunology

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For immune diagnostic purposes it would be critical to be able to distinguish between ongoing immune processes, such as active infections, and long-term immune memory, for example imprinted by infections that have been cleared a long time ago or by vaccinations. We tested the hypothesis that the secretion of Granzyme B, as detected in ex vivo ELISPOT assays, permits this distinction. We studied EBV-, flu-and CMV-specific CD8 + cells in healthy individuals, Vaccinia virus-reactive CD8 + cells in the course of vaccination, and HIV-specific CD8 + cells in HIV-infected individuals. Antigen-specific ex vivo GzB production was detected only transiently after Vaccinia immunization, and in HIV-infected individuals. Our data suggest that ex vivo ELISPOT measurements of granzyme B permit the identification of actively ongoing CD8 + cell responses -a notion that is pertinent to the immune diagnostic of infections, transplantation, allergies, autoimmune diseases, tumors, and vaccine development.

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Comprehensive Determinant Mapping of the Hepatitis C-Specific CD8 Cell Repertoire Reveals Unpredicted Immune Hierarchy

Cited by 24 publications

References 48 publications

Suppression of HCV-specific T cells without differential hierarchy demonstrated in persistent HCV infection

Suppression of HCV-specific T cells without differential hierarchy demonstrated in persistent HCV infection

Kinetics of the immune response during HBV and HCV infection

Granzyme B production distinguishes recently activated CD8+ memory cells from resting memory cells

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