The Immunodominant, Ld-Restricted T Cell Response to Hepatitis B Surface Antigen (HBsAg) Efficiently Suppresses T Cell Priming to Multiple Dd-, Kd-, and Kb-Restricted HBsAg Epitopes

Hepatitis B virus (HBV) infection is a worldwide public health problem. HBV-specific CD8+ CTLs are vital for viral clearance. Identification of immunodominant CTL epitopes from HBV-associated antigens is necessary for therapeutic vaccine development. We showed that the HLA-A*1101 allele is one of the most common alleles in both healthy individuals and chronic hepatitis B (CHB) patients in the Chongqing area, China. However, less than 10 % of epitopes of HBV-associated antigens have been identified in an HLA-A*1101 context. Here, we describe an immunodominant CD8+ T-cell response targeting a hepatitis B surface antigen determinant (HBs295–304) restricted by HLA-A*1101 in both healthy individuals and CHB patients. Moreover, HBs295–304 is more immunogenic for CTL induction than a known naturally HLA-A*1101-processed epitope from hepatitis B core antigen (HBc88–96). Therefore, the newly identified epitope, HBs295–304, will benefit the development of immunotherapeutic approaches for HBV infection.

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The Size of the Viral Inoculum Contributes to the Outcome of Hepatitis B Virus Infection

Journal of Virology ◽

10.1128/jvi.00867-09 ◽

2009 ◽

Vol 83 (19) ◽

pp. 9652-9662 ◽

Cited By ~ 167

Author(s):

Shinichi Asabe ◽

Stefan F. Wieland ◽

Pratip K. Chattopadhyay ◽

Mario Roederer ◽

Ronald E. Engle ◽

...

Keyword(s):

Hepatitis B Virus ◽

T Cell ◽

Hepatitis B ◽

Cell Response ◽

T Cell Response ◽

Cd4 T Cell ◽

Viral Spread ◽

B Virus ◽

T Cell Priming ◽

Kinetics Of

ABSTRACT The impact of virus dose on the outcome of infection is poorly understood. In this study we show that, for hepatitis B virus (HBV), the size of the inoculum contributes to the kinetics of viral spread and immunological priming, which then determine the outcome of infection. Adult chimpanzees were infected with a serially diluted monoclonal HBV inoculum. Unexpectedly, despite vastly different viral kinetics, both high-dose inocula (1010 genome equivalents [GE] per animal) and low-dose inocula (10° GE per animal) primed the CD4 T-cell response after logarithmic spread was detectable, allowing infection of 100% of hepatocytes and requiring prolonged immunopathology before clearance occurred. In contrast, intermediate (107 and 104 GE) inocula primed the T-cell response before detectable logarithmic spread and were abruptly terminated with minimal immunopathology before 0.1% of hepatocytes were infected. Surprisingly, a dosage of 101 GE primed the T-cell response after all hepatocytes were infected and caused either prolonged or persistent infection with severe immunopathology. Finally, CD4 T-cell depletion before inoculation of a normally rapidly controlled inoculum precluded T-cell priming and caused persistent infection with minimal immunopathology. These results suggest that the relationship between the kinetics of viral spread and CD4 T-cell priming determines the outcome of HBV infection.

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Recombinant hepatitis B large surface antigen, successfully produced in Escherichia coli, stimulates T-cell response in mice

Vaccine ◽

10.1016/j.vaccine.2006.02.048 ◽

2006 ◽

Vol 24 (20) ◽

pp. 4409-4416 ◽

Cited By ~ 2

Author(s):

Li Shu ◽

Neal Touzjian ◽

Deng Nan ◽

Nicholas Kushner ◽

Amie J. Strong ◽

...

Keyword(s):

Escherichia Coli ◽

T Cell ◽

Hepatitis B ◽

Surface Antigen ◽

Cell Response ◽

T Cell Response ◽

Recombinant Hepatitis

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Mimicry of the a determinant of hepatitis B surface antigen by an antiidiotypic antibody. I. Evaluation in hepatitis B surface antigen responder and nonresponder strains.

Journal of Experimental Medicine ◽

10.1084/jem.177.1.127 ◽

1993 ◽

Vol 177 (1) ◽

pp. 127-134 ◽

Cited By ~ 10

Author(s):

M W Pride ◽

A Thakur ◽

Y Thanavala

Keyword(s):

Immune Response ◽

T Cells ◽

Lymph Node ◽

T Cell ◽

Hepatitis B ◽

Surface Antigen ◽

Hepatitis B Surface Antigen ◽

T Cell Response

B and T cell responses of several strains of mice, immunized with a monoclonal antiidiotype (anti-Id) that mimics the a determinant of hepatitis B surface antigen (HBsAg), were studied to determine if the immune response to the anti-Id was regulated by H-2-linked immune response genes as has been previously observed for HBsAg. We report that immunization with anti-Id could elicit HBsAg-specific antibodies in mice of the H-2d,q, or f haplotype and in an outbred wild mouse strain (Mus spretus), thus circumventing the H-2 haplotype restriction pattern observed when immunizing with HBsAg in H-2f mice. Purified lymph node T cells from mice of the H-2d or q haplotype and M. spretus that were primed in vivo with HBsAg or anti-Id could be stimulated in vitro with either HBsAg or anti-Id but not with an irrelevant antibody of the same subclass as the anti-Id. However, purified lymph node T cells from H-2f mice that were primed in vivo with the anti-Id could only be stimulated in vitro with anti-Id. No in vitro stimulation whatsoever was observed in H-2f mice immunized with HBsAg. The effect of processing and presentation of the anti-Id by antigen-presenting cells (APC) was studied in mice of the H-2d haplotype. Stimulation of purified lymph node T cells by HBsAg and anti-Id was shown to be strictly dependent on APC and restricted by major histocompatibility complex class II antigens at the I-A locus. Treatment of APC with paraformaldehyde or chloroquine abrogated the T cell response to all antigens except for a nine-amino acid synthetic peptide representing a partial analogue of the group a determinant of HBsAg S(139-147). The significance of these results is discussed in the context of understanding the mechanism of mimicry elicited by the anti-Id.

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