Purification and characterization of a naturally processed hepatitis B virus peptide recognized by CD8+ cytotoxic T lymphocytes.

Tsai, Shau‐Wei; Chen, Ming-Huei; Yeh, Chi-Ju; Chu, Chia–Ming; Lin, Ae-Ning; Chiou, Fu-Horng; Chang, Tang‐Hsien; Liaw, Yun–Fan

doi:10.1172/jci118450

Cited by 72 publications

(40 citation statements)

References 46 publications

(41 reference statements)

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“…A comprehensive knowledge of HBV-specific CD8 ϩ T-cell specificities is lacking, and with rare exceptions (7,9,43), CD8 ϩ T-cell responses have been analyzed using preselected peptides able to bind to common HLA class I molecules (HLA-A2, -A3, -A24, -A11, and -B7) (19,20,26,31,32,38,43,45). Attempts to define immunodominant regions in the HBV proteome were based on the use of HLA-A2-restricted epitopes (45) and on samples from HBV genotype A (HBV genA )-or HBV genD -infected individuals of Caucasian decent.…”

Section: Virus-specific Cd8mentioning

confidence: 99%

Host Ethnicity and Virus Genotype Shape the Hepatitis B Virus-Specific T-Cell Repertoire

Tan

Loggi

Boni

et al. 2008

J Virol

110

107

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Repertoire composition, quantity, and qualitative functional ability are the parameters that define virusspecific T-cell responses and are linked with their potential to control infection. We took advantage of the segregation of different hepatitis B virus (HBV) genotypes in geographically and genetically distinct host populations to directly analyze the impact that host and virus variables exert on these virus-specific T-cell parameters. T-cell responses against the entire HBV proteome were analyzed in a total of 109 HBV-infected subjects of distinct ethnicities (47 of Chinese origin and 62 of Caucasian origin). We demonstrate that HBV-specific T-cell quantity is determined by the virological and clinical profiles of the patients, which outweigh any influence of race or viral diversity. In contrast, HBV-specific T-cell repertoires are divergent in the two ethnic groups, with T-cell epitopes frequently found in Caucasian patients seldom detected in Chinese patients. In conclusion, we provide a direct biological evaluation of the impact that host and virus variables exert on virus-specific T-cell responses. The discordance between HBV-specific CD8 T-cell repertoires present in Caucasian and Chinese subjects shows the ability of HLA micropolymorphisms to diversify T-cell responses and has implications for the rational development of therapeutic and prophylactic vaccines for worldwide use.

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Section: Virus-specific Cd8mentioning

confidence: 99%

Host Ethnicity and Virus Genotype Shape the Hepatitis B Virus-Specific T-Cell Repertoire

Tan

Loggi

Boni

et al. 2008

J Virol

110

107

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“…The P2 peptide exhibited activity in sensitizing target cells for lysis by CD8 ϩ CTLs. The P2 sequence, similar to that of HBcAg 88 -96 , contained the HLA-A11 binding motifs (12). Moreover, the 7-mer peptide epitope was also found in H-2d mice immunized with HBcAg 87-95 peptide (SYVNTNMGL) (13).…”

mentioning

confidence: 93%

“…Previously, we isolated an HBV-specific 7-mer peptide (YVNTNMG) that was bound with gp96 from the liver tissue of HCC patients infected with HBV (10) using a three-step purification method (11). This peptide shares sequence homology with a naturally processed peptide Ag, P2 (YVNVNMGLK), that was isolated from the HLA class I molecules on the cell membrane of HBV-infected liver (12). The P2 peptide exhibited activity in sensitizing target cells for lysis by CD8 ϩ CTLs.…”

mentioning

confidence: 99%

Generation of Murine CTL by a Hepatitis B Virus-Specific Peptide and Evaluation of the Adjuvant Effect of Heat Shock Protein Glycoprotein 96 and Its Terminal Fragments

Zhou

Han

et al. 2005

The Journal of Immunology

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Previously, we reported that a 7-mer HLA-A11-restricted peptide (YVNTNMG) of hepatitis B virus (HBV) core Ag (HBcAg88–94) was associated with heat shock protein (HSP) gp96 in liver tissues of patients with HBV-induced hepatocellular carcinoma (HCC). This peptide is highly homologous to a human HLA-A11-restricted 9-mer peptide (YVNVNMGLK) and to a mouse H-2-Kd-restricted 9-mer peptide (SYVNTNMGL). To further characterize its immunogenicity, BALB/c mice were vaccinated with the HBV 7-mer peptide. It was found that a specific CTL response was induced by the 7-mer peptide, although the response was ∼50% of that induced by the mouse H-2-Kd-restricted 9-mer peptide, as detected by ELISPOT, tetramer, and 51Cr release assays. To evaluate the adjuvant effect of HSP gp96, mice were coimmunized with gp96 and the 9-mer peptide, and a significant adjuvant effect was observed with gp96. To further determine whether the immune effect of gp96 was dependent on peptide binding, the N- and C-terminal fragments of gp96, which are believed to contain the putative peptide-binding domain, were cloned and expressed in Escherichia coli. CTL assays indicated that only the N-terminal fragment, but not the C-terminal fragment, was able to produce the adjuvant effect. These results clearly demonstrated the potential of using gp96 or its N-terminal fragment as a possible adjuvant to augment CTL response against HBV infection and HCC.

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“…These peptides may contribute to the antigen component of a vaccine and to the design of assays for use as correlates of immunity in trials of antiviral therapies. Although some of the HBV peptides that bind to four HLA-A alleles have been published (3,19,25,28), a much wider repertoire of peptide-HLA interactions needs to be identified. There is no established method for finding them (32).…”

mentioning

confidence: 99%

Associations between HLA Class I Alleles and Escape Mutations in the Hepatitis B Virus Core Gene in New Zealand-Resident Tongans

Abbott

Tsai

Leung

et al. 2010

J Virol

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The full repertoire of hepatitis B virus (HBV) peptides that bind to the common HLA class I molecules found in areas with a high prevalence of chronic HBV infection has not been determined. This information may be useful for designing immunotherapies for chronic hepatitis B. We identified amino acid residues under positive selection pressure in the HBV core gene by phylogenetic analysis of cloned DNA sequences obtained from HBV DNA extracted from the sera of Tongan subjects with inactive, HBeAg-negative chronic HBV infections. The repertoires of positively selected sites in groups of subjects who were homozygous for either HLA-B*4001 (n ‫؍‬ 10) or HLA-B*5602 (n ‫؍‬ 7) were compared. We identified 13 amino acid sites under positive selection pressure. A significant association between an HLA class I allele and the presence of nonsynonymous mutations was found at five of these sites. HLA-B*4001 was associated with mutations at E77 (P ‫؍‬ 0.05) and E113 (P ‫؍‬ 0.002), and HLA-B*5602 was associated with mutations at S21 (P ‫؍‬ 0.02). In addition, amino acid mutations at V13 (P ‫؍‬ 0.03) and E14 (P ‫؍‬ 0.01) were more common in the seven subjects with an HLA-A*02 allele. In summary, we have developed an assay that can identify associations between HLA class I alleles and HBV core gene amino acids that mutate in response to selection pressure. This is consistent with published evidence that CD8 ؉ T cells have a role in suppressing viral replication in inactive, HBeAg-negative chronic HBV infection. This assay may be useful for identifying the clinically significant HBV peptides that bind to common HLA class I molecules.The most potent nucleoside/nucleotide analogue drugs used to treat chronic hepatitis B reduce serum hepatitis B virus (HBV) DNA to undetectable levels in over 90% of subjects (5, 10). It was originally hoped that such a substantial reduction in viral titers would reverse T-cell tolerance for HBV antigens (17, 30) and lead to an immune response that permanently suppressed the virus, thus removing the need for expensive, lifelong drug therapy. However, HBeAg seroconversion rates of under 30% suggest that suppression of HBV replication is not sufficient to reverse the defects (4, 15) in the HBV peptidespecific CD8 ϩ T-cell compartment that occur in these patients. A therapeutic vaccine that stimulated a diverse repertoire of functional CD8 ϩ T cells could make a valuable contribution to management of chronic hepatitis B.The first step in designing a therapeutic vaccine that will suppress viral replication without exacerbating chronic hepatitis B (15) is to identify the HBV peptides that stimulate functional CD8 ϩ T cells by binding to the most common HLA class I alleles. These peptides may contribute to the antigen component of a vaccine and to the design of assays for use as correlates of immunity in trials of antiviral therapies. Although some of the HBV peptides that bind to four HLA-A alleles have been published (3,19,25,28), a much wider repertoire of peptide-HLA interactions needs to be identified. T...

show abstract

Purification and characterization of a naturally processed hepatitis B virus peptide recognized by CD8+ cytotoxic T lymphocytes.

Cited by 72 publications

References 46 publications

Host Ethnicity and Virus Genotype Shape the Hepatitis B Virus-Specific T-Cell Repertoire

Host Ethnicity and Virus Genotype Shape the Hepatitis B Virus-Specific T-Cell Repertoire

Generation of Murine CTL by a Hepatitis B Virus-Specific Peptide and Evaluation of the Adjuvant Effect of Heat Shock Protein Glycoprotein 96 and Its Terminal Fragments

Associations between HLA Class I Alleles and Escape Mutations in the Hepatitis B Virus Core Gene in New Zealand-Resident Tongans

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