Mapping of immunodominant CD4+ T lymphocyte epitopes of hepatitis C virus antigens and their relevance during the course of chronic infection

Hoffmann, Robert M.; Diepolder, Helmut M.; Zachoval, Reinhart; Zwiebel, Franz-Maximilian; Jung, Maria–Christina; Scholz, Siegfried; Nitschko, Hans; Riethmüller, Gert; Pape, Gerd R.

doi:10.1002/hep.1840210305

Cited by 104 publications

(96 citation statements)

References 18 publications

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“…25 Hoffman et al have shown that the presence of HCV-specific CD4 ϩ response in peripheral circulation may be associated with a favorable response to IFN therapy. 26 They also reported that sustained responders to IFN were more likely to have peripheral HCV-specific CD4 ϩ activity. Theoretically, the host should have coordinated CD4 ϩ and CD8 ϩ CTL responses to combat HCV infection.…”

Section: Discussionmentioning

confidence: 99%

Intrahepatic hepatitis C virus-specific cytotoxic T lymphocyte activity and response to interferon alfa therapy in chronic hepatitis C

et al. 1998

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Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes (CTL) have been shown to play a role in host defense and pathogenesis of chronic HCV infection. Our aim was to test the hypothesis that intrahepatic HCV-specific CTL activity may impact subsequent response to interferon alfa (IFN-␣) therapy. Of the 37 patients that we have prospectively evaluated for HCV-specific CTL activity in liver, 21 received IFN therapy, and 19 completed a 6-month course and attended 6 to 18 months of follow-up. Intrahepatic CD8 ؉ cells were isolated from liver biopsy tissue and tested against target cells expressing HCV antigens to determine intrahepatic CTL activity. The relationship between treatment response and HCV-specific CTL activity and other factors known to associate with response (genotype, viremia, histology) was analyzed. HCV-specific CTL activity was detected in 9 of 21 patients (and 9 of 19 who completed therapy). After 6 months of IFN therapy, 8 of 19 (42%) patients had normal serum alanine transaminase (ALT) (complete responders). After 18 months of follow-up, only 3 patients (16%) had a sustained biochemical response. Of the 9 patients with detectable HCV-specific CTL activity in their liver before treatment, 7 (78%) developed a complete response. In contrast, only 1 of the 10 patients with no detectable HCV-specific CTL activity developed a complete response to IFN (P F .01). In 6 of 8 patients with a complete response, including the 3 sustained responders, the CTL response appeared to be directed predominately to the HCV core region. These data suggest that the host immune response, particularly that mediated by CD8 ؉ CTL, may be important in determining the outcome of IFN therapy for chronic HCV infection. Further understanding of the mechanism of action of IFN should impact the design of better therapeutic strategies against chronic HCV infection. (HEPATOLOGY 1998;28:225-230.)The host cellular immune defense, including the CD4 ϩ and CD8 ϩ T-cell response, is activated in patients with hepatitis C virus (HCV) infection. The intensity of the T-cell response during the early stages of infection may be a critical determinant of disease resolution and control of infection. 1,2 In chronic viral infection, viral-specific CD8 ϩ cytotoxic T lymphocytes (CTL) have been shown to be important in host defense and in the control of the viral infection. [3][4][5][6][7] In lymphocytic choriomeningitis virus infection, virus-specific CTL activity reduces viral titers by 4 to 5 logs. 8 It is felt that CTL might lead to viral clearance through either direct lysis of infected cells or cytokine-mediated mechanisms. We and others have shown that HCV-specific CTL activity is detectable in the liver in a proportion of patients with chronic HCV infection. The presence of HCV-specific CTL activity in bulk-expanded CTL was found to be associated with a lower level of viremia and a greater inflammatory activity in the liver, suggesting that HCV-specific CTLs may assist in the control HCV infection, but, in so doing, contribute to hepatoce...

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Section: Discussionmentioning

confidence: 99%

Intrahepatic hepatitis C virus-specific cytotoxic T lymphocyte activity and response to interferon alfa therapy in chronic hepatitis C

et al. 1998

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“…However, they are weak and inefficient [3][4][5][6][7][8][9][10]14,15,45]. In fact, the frequency of CTL precursors against HCV proteins found in patients with chronic hepatitis C is very low, in comparison to that found in HIV or CMV infections [46][47][48].…”

Section: Discussionmentioning

confidence: 99%

“…It is characterised by a high tendency to chronicity, which often progresses to cirrhosis and liver cancer [2]. Viral clearance after acute hepatitis or after IFN-␣ therapy is usually associated with strong CD4 and CD8 T cell responses [3][4][5][6][7][8][9][10][11][12]. In particular, cellular T helper immune response against nonstructural NS3 HCV protein has been associated with viral clearance after acute infection, whereas absence of this Tcell response leads to viral persistence and chronic hepatitis [9,13].…”

Section: Introductionmentioning

confidence: 99%

Enhancement of CD4 and CD8 immunity by anti-CD137 (4-1BB) monoclonal antibodies during hepatitis C vaccination with recombinant adenovirus

Arribillaga

Sarobe

Arina

et al. 2005

Vaccine

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The induction of protective or therapeutic cellular immunity against hepatitis C virus (HCV) is a difficult goal. In a previous work we showed that immunization with a recombinant adenovirus encoding HCV-NS3 (RAdNS3) could partially protect mice from challenge with a vaccinia virus encoding HCV antigens. We sought to investigate whether systemic administration of an immunostimulatory monoclonal antibody directed against the lymphocyte surface molecule CD137 could enhance the immunity elicited by RAdNS3. It was found that treatment with anti-CD137 mAb after the administration of a suboptimal dose of RAdNS3 enhanced cytotoxic and T helper cell responses against HCV NS3. Importantly, the ability of RAdNS3 to induce protective immunity against challenge with a recombinant vaccinia virus expressing HCV proteins was markedly augmented. Thus, combination of immunostimulatory anti-CD137 mAb with recombinant adenoviruses expressing HCV proteins might be useful in strategies of immunization against HCV.

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“…Indeed, several reports illustrate that viral clearance during acute HCV infection is associated with a multispecific CD4 ϩ T-cell response that is much less vigorous in chronically infected patients. 6,8,9,[25][26][27][28][29] Gerlach et al have recently reported that the CD4 ϩ T-cell response persists in acutely infected subjects who permanently clear the virus, whereas it disappears in patients who initially control the infection but in whom it subsequently recurs, suggesting that the CD4 ϩ T-cell response must be maintained permanently to achieve long-term control of HCV. 25 The interdependence of CD4 ϩ and CD8 ϩ T-cell responses has been well described in several viral infections.…”

mentioning

confidence: 99%

Differential CD4+ and CD8+ T-cell responsiveness in hepatitis C virus infection

2001

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This study was performed to compare the vigor and phenotype of virus-specific CD4 ؉ and CD8 ؉ T-cell responses in patients with different virologic and clinical outcomes after hepatitis C virus (HCV) infection. The results show that a vigorous and multispecific CD4 ؉ proliferative T-cell response is maintained indefinitely after recovery from HCV infection whereas it is weak and focused in persistently infected patients. In contrast, the HCV-specific CD8 ؉ T-cell response was quantitatively low in both groups despite the use of sensitive direct ex vivo intracellular interferon gamma (IFN-␥) staining. Furthermore, although HCV-specific cytolytic CD8 ؉ memory T cells were undetectable ex vivo, they were readily expanded from the peripheral blood of chronically HCV-infected patients but not from recovered subjects after in vitro stimulation, suggesting that ongoing viremia is required to maintain the HCV-specific memory CD8 ؉ T-cell response. HCV-specific CD8 ؉ T cells displayed a type 1 cytokine profile characterized by production of IFN-␥ despite persistent HCV viremia. The paradoxical observation that HCV-specific CD4 ؉ T cells survive and CD8 ؉ T cells are lost after viral clearance while the opposite occurs when HCV persists suggests the existence of differential requirements for the maintenance of CD4 ؉ and CD8 ؉ T-cell memory during HCV infection. Furthermore, the relative rarity of circulating CD8 ؉ effector T cells in chronically infected patients may explain the chronic insidious nature of the liver inflammation and also why they fail to eliminate the virus. (HEPATOLOGY 2001;33:267-276.)Hepatitis C virus (HCV) is a parenterally transmitted hepatotropic RNA virus that causes acute and chronic hepatitis. 1,2 While acute infection is generally subclinical, and therefore difficult to identify, chronic infection occurs in the majority of cases, and this can be associated with chronic hepatitis, cirrhosis, and hepatocellular carcinoma. 3,4 The role of CD4 ϩ and CD8 ϩ T cells in HCV clearance or disease pathogenesis is not well understood. Certainly, persistent infection occurs despite the presence of virus-specific CD4 ϩ and CD8 ϩ T cells in the liver and the peripheral blood, suggesting that these responses are ineffective in most patients. [5][6][7][8][9][10][11][12] The CD8 ϩ T-cell response to HCV may be only partially successful in virus control because it is quantitatively inadequate, [13][14][15][16][17] and it may also select for immune escape variants that further contribute to viral persistence. 13,[18][19][20] The role of CD8 ϩ T cells in this infection is most clearly illustrated, perhaps, in experimentally infected chimpanzees where a multispecific intrahepatic HCV-specific CD8 ϩ T-cell response during the early phase of infection was associated with subsequent HCV clearance while a more narrowly focused and delayed response was associated with persistent infection. 21 In contrast to these results, however, the relationship between the HCV-specific CD8 ϩ T-cell response and the outcome of infection...

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Mapping of immunodominant CD4+ T lymphocyte epitopes of hepatitis C virus antigens and their relevance during the course of chronic infection

Cited by 104 publications

References 18 publications

Intrahepatic hepatitis C virus-specific cytotoxic T lymphocyte activity and response to interferon alfa therapy in chronic hepatitis C

Intrahepatic hepatitis C virus-specific cytotoxic T lymphocyte activity and response to interferon alfa therapy in chronic hepatitis C

Enhancement of CD4 and CD8 immunity by anti-CD137 (4-1BB) monoclonal antibodies during hepatitis C vaccination with recombinant adenovirus

Differential CD4+ and CD8+ T-cell responsiveness in hepatitis C virus infection

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