Why do cytotoxic T lymphocytes fail to eliminate hepatitis C virus? Lessons from studies using major histocompatibility complex class I peptide tetramers

Lechner, Franziska; Sullivan, John S.; Spiegel, Hans; Nixon, Douglas F.; Ferrari, Belinda C.; Davis, Andrew R.; Borkowsky, Bill; Pollack, Henry; Barnes, Eleanor; Dusheiko, G.; Klenerman, Paul

doi:10.1098/rstb.2000.0646

Cited by 28 publications

(22 citation statements)

References 44 publications

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“…Work using tetramers derived from HLA-B8 and -B7 restricted peptides has given similar results to A2-based tetramers, i.e. most persistently infected patients show weak or absent responses [9,62]. Table 2 shows the variability of some of these epitopes, dependent on viral genotype.…”

Section: Hcv-specific Epitopes -The Evidence Basementioning

confidence: 74%

Cellular immune responses against hepatitis C virus: the evidence base 2002

Ward¹,

Lauer

Isba³

et al. 2002

Clinical and Experimental Immunology

141

102

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SUMMARYHepatitis C virus (HCV) is an RNA virus which is estimated to persistently infect about 170 million people worldwide. After acute infection, there is an initial period during which long-term outcome is decided. There is strong evidence that the cellular immune responses, involving both CD4 + and CD8 + T lymphocytes, are involved at this stage and it is their effectiveness which determines outcome. What is not understood is what determines their effectiveness. The most important component of this is likely to be some aspect of epitope selection, itself dictated by host MHC. Thus, to understand host immunity to HCV, we need to have a detailed understanding of the peptides involved in T lymphocyte responses. In this review, we discuss the peptide epitopes that have been identified so far, and their potential significance. We relate this to a scheme of host defence which may be useful for understanding natural and vaccine-induced immunity.

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Section: Hcv-specific Epitopes -The Evidence Basementioning

confidence: 74%

Cellular immune responses against hepatitis C virus: the evidence base 2002

Ward¹,

Lauer

Isba³

et al. 2002

Clinical and Experimental Immunology

141

102

View full text Add to dashboard Cite

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“…HCV-SP were harvested at 3 days postinfection as described above. The internalization experiment was performed by incubating 100 g of 35 S-labeled HCV-SP per 2 ϫ 10 8 cells/well in a six-well plate for 15, 30, or 60 min at 37°C. (ii) Method with dye-labeled material.…”

Section: Methodsmentioning

confidence: 99%

“…5A). To test more di- 35 S-labeled methionine-cysteine mix. HCV-SP was prepared as described previously and then purified, and radiolabeled material (50 g/ml) was incubated with HepG2 cells at 37°C for the indicated times.…”

Section: Cell Binding Of Hcv-sp/p7(؉) and Hcv-sp/p7(؊)mentioning

confidence: 99%

“…These data suggest that the presentation of envelope antigens by target cells is probably a critical event that leads to recognition by the immune system and triggers the appropriate response. Nevertheless, viral antigen presentation does not lead to significant production of neutralizing anti-HCV antibodies in chronic hepatitis C infections or to a sustained, vigorous cytotoxic-Tlymphocyte (CTL) response (35,51).…”

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confidence: 99%

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Role of the Asialoglycoprotein Receptor in Binding and Entry of Hepatitis C Virus Structural Proteins in Cultured Human Hepatocytes

Saunier

Triyatni

Ulianich

et al. 2003

J Virol

118

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We used a baculovirus-based system to prepare structural proteins of hepatitis C virus (HCV) genotype 1a. Binding of this preparation to cultured human hepatic cells was both dose dependent and saturable. This binding was decreased by calcium depletion and was partially prevented by ligands of the asialoglycoprotein receptor (ASGP-R), thyroglobulin, asialothyroglobulin, and antibody against a peptide in the carbohydrate recognition domain of ASGP-R but not preimmune antibody. Uptake by hepatocytes was observed with both radiolabeled and dye-labeled HCV structural proteins. With hepatocytes expressing the hH1 subunit of the ASGP-R fused to green fluorescent protein, we could show by confocal microscopy that dye stain cointernalized with the fusion protein in an area surrounding the nucleus. Internalization was more efficient with a preparation containing p7 than with one that did not. The two preparations bound to transfected 3T3-L1 cells expressing either both (hH1 and hH2) subunits of the ASGP-R (3T3-22Z cells) or both hH1 and a functionally defective variant of hH2 (3T3-24X cells) but not to parental cells. Additionally, uptake of dye-labeled preparation containing p7 was observed with 3T3-22Z cells but not with 3T3-L1 or 3T3-24X cells or with the preparation lacking p7, suggesting that p7 regulates the internalization properties of HCV structural proteins. Our observations suggest that HCV structural proteins bind to and cointernalize with the ASGP-R in cultured human hepatocytes.Hepatitis C virus (HCV) infection has become a major health problem affecting an estimated 170 million people worldwide. Persistent infection occurs in more than 70% of people infected with HCV, which may be complicated by cirrhosis and/or hepatocellular carcinoma (24, 33). Despite highly competitive and extensive research in this field, a highly effective treatment is not yet available. The mainstay of anti-HCV therapy, alpha interferon (IFN-␣) or pegylated IFN-␣, together with ribavirin leads, at best, to viral clearance in ca. 41 to 54% of patients infected with HCV genotype 1a (34,38). Since mechanisms of HCV infection remain unclear, characterization of these mechanisms is now a major issue for the development of new strategies for anti-HCV treatment and prevention.

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“…4 Although there is still some debate over what constitutes protective immunity against HCV infection, recent data suggest that both CD4 + and CD8 + T cell responses are required for clearance of the acute infection. [5][6][7][8][9][10][11] A broad and robust HCV-specific CD4 + and CD8 + cellular immune response also appears to be important in clearance of chronic HCV infection during treatment with interferon-α and robavirin. 12 This concept is supported by the observation that individuals with chronic infection are often found to have relatively weak and narrowly directed CD4 + and CD8 + T cell responses against HCV.…”

Section: Introductionmentioning

confidence: 99%