Cytotoxic T lymphocytes recognize an HLA-A2-restricted epitope within the hepatitis B virus nucleocapsid antigen.

Penna, Amalia; Chisari, Francis V.; Bertoletti, Antonio; Missale, Gabriele; Fowler, P; Giuberti, T.; Fiaccadori, F; Ferrari, Carlo

doi:10.1084/jem.174.6.1565

Cited by 345 publications

(196 citation statements)

References 23 publications

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“…16,71 However, peripheral blood virus-specific T-cell responses have been well-correlated with clinical or virologic outcomes in many studies of hepatitis B virus and HCV infection, supporting the possible relevance of our observations. 8,11,[13][14][15]17,22,25,26,29,43,44,46,69,70,72,73 Another intriguing consideration is that the CTL epitope repertoire may differ between patients who clear HCV and those who do not. Furthermore, the pattern of CTL immunodominance may be influenced by epitope mutations, as shown in human immunodeficiency virus infection.…”

Section: Discussionmentioning

confidence: 99%

“…In general, successful viral clearance is associated with a vigorous antiviral T-cell response whereas persistent infection is associated with a weak or narrowly focused T-cell response, as amply shown in hepatitis B virus, [43][44][45][46] human immunodeficiency virus, 39,[47][48][49][50][51] and murine lymphocytic choriomeningitis virus infections. 52,53 Both CD4 ϩ and CD8 ϩ T cells contribute to virus control.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

2001

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“…16,20,21 Studies on virus-specific CTL derived from the peripheral blood or liver of patients infected with hepatitis B virus strongly underline the importance of the CTL response in mediating virus clearance from acutely infected patients and indicate that failure to mount a strong CTL response may lead to chronic hepatitis B. [36][37][38] Hepatitis B virus (HBV) replication in HBV transgenic mice is inhibited by intraperitoneal application of IL-12, 39 further supporting the concept that the Th1 differentiation pathway plays a pivotal role in eradication of HBV infection. 40,41 A striking clinical feature of HCV infection is that approximately 70% to 80% of patients with acute hepatitis C will develop chronic infection.…”

Section: Discussionmentioning

confidence: 99%

A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis C

et al. 1999

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“…Extracellular viral antigens are bound by anti-HBs antibodies, indicating acquired immunity after viral clearance in the case of self-limited disease. The chronic carrier state, however, is characterized by virus persistence, a lower frequency of cytotoxic T cells to HBV structural antigens, and the lack of anti-HBs antibodies in the serum [2,4,5].…”

Section: Introductionmentioning

confidence: 99%

Regulation of the neutralizing anti-hepatitis B surface (HBs) antibody response in vitro in HBs vaccine recipients and patients with acute or chronic hepatitis B virus (HBV) infection

Böcher

Herzog-Hauff

Herr

et al. 1996

Clinical and Experimental Immunology

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SUMMARYAntibodies directed to the HBs antigen indicate viral clearance and the development of life-long immunity in patients that recovered from HBV infection. In HBs antigen vaccine recipients anti-HBs antibodies provide protective immunity. However, little is known about the regulation of this HBsspecific antibody response. The existence of anti-HBs-secreting B cells was demonstrated using the highly sensitive ELISPOT technique compared with conventional ELISA in serum and cell culture supernatants. In the peripheral blood of patients with acute self-limited hepatitis B, HBs-specific B cells were demonstrated with a high frequency despite undetectable anti-HBs serum antibodies. HBVimmunized patients that had recovered from infection and vaccine recipients had significantly lower frequencies, whereas chronic HBV carriers and negative controls showed no anti-HBs-secreting B cells. Coculture experiments of isolated B and T cells revealed that the anti-HBs antibody response was restricted to the presence of T helper cells, but not to identical HLA class II molecules. Allogeneic T cells derived from vaccine recipients or chronic HBV carriers stimulated the HBs-specific B cell response in HBs vaccine recipients. Otherwise, isolated T helper cells could never provide sufficient help to induce the HBs-specific B cell response in chronic HBV carriers. Furthermore, peripheral blood mononuclear cells (PBMC) of six out of 10 vaccine recipients, one out of five HBV-immunized patients, but of no chronic HBV carrier showed a proliferative response to different HBs antigen preparations. This study demonstrated a high frequency of circulating anti-HBs-producing B cells in the early phase of acute HBV infection, but a lower frequency of HBs-specific B cells years after resolution of HBV infection. In chronic HBV carriers, however, deficient HBs-specific T and B cell responses were observed.

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Cytotoxic T lymphocytes recognize an HLA-A2-restricted epitope within the hepatitis B virus nucleocapsid antigen.

Cited by 345 publications

References 23 publications

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

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

A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis C

Regulation of the neutralizing anti-hepatitis B surface (HBs) antibody response in vitro in HBs vaccine recipients and patients with acute or chronic hepatitis B virus (HBV) infection

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