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Cytotoxic T lymphocyte responses and CTL epitope escape mutation in HBsAg, anti-HBe positive individuals

Abstract

BACKGROUND/AIMS Clearance of hepatitis B virus (HBV) is characterised by a strong cytotoxic T cell response. Persistence of HBV in chronic hepatitis B carriers may be related to failure of this response. The aim of this study was to determine whether HLA class I restricted cytotoxic T lymphocyte (CTL) responses persist in anti-hepatitis B e (HBe) positive / HBV DNA negative individuals, and to correlate the presence of viral CTL epitope mutation with clinical outcome.

METHODS An HLA/HBV dual transfectant model was used to demonstrate these CTL responses in individuals chronically infected with HBV. Subsequently, a known hepatitis B core (HBc) CTL epitope was sequenced in a family of five chronically infected individuals all sharing a HLA allele (HLA-A68.1).

RESULTS Low level HLA class I restricted cytotoxic T cell responses were detected in the peripheral blood of five of eight anti-HBe positive individuals. In the family of HLA-A68.1 positive chronically infected individuals, mutation of the HLA-A68.1 restricted hepatitis B core antigen (HBcAg) CTL epitope STLPETTVVRR was found in all four anti-HBe positive individuals but not in the sole hepatitis B e antigen (HBeAg) positive patient.

CONCLUSION These data are consistent with a continued immune selection pressure on HBV in anti-HBe positive chronically infected individuals with low replicating HBV infection and suggest that mutation of a CTL epitope may be a consequence of the immune response, as opposed to the cause of viral persistence.

  • hepatitis B virus
  • HLA
  • hepatitis B core antigen
  • cytotoxicity
  • mutant
  • Abbreviations used in this paper

    HBV
    hepatitis B virus
    CTL
    cytotoxic T lymphocyte
    PCR
    polymerase chain reaction
    HBe
    hepatitis B e
    HBeAg
    hepatitis B e antigen
    HBsAg
    hepatitis B surface antigen
    MHC
    major histocompatibility complex
    ALT
    alanine aminotranferase
    HIV
    human immunodeficiency virus
    HBc
    hepatitis B core
    HBcAg
    hepatitis B core antigen
    FACS
    fluorescence activated cell sorter
    ELISA
    enzyme linked immunosorbent assay
    PBMC
    peripheral blood mononuclear cells
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  • Abbreviations used in this paper

    HBV
    hepatitis B virus
    CTL
    cytotoxic T lymphocyte
    PCR
    polymerase chain reaction
    HBe
    hepatitis B e
    HBeAg
    hepatitis B e antigen
    HBsAg
    hepatitis B surface antigen
    MHC
    major histocompatibility complex
    ALT
    alanine aminotranferase
    HIV
    human immunodeficiency virus
    HBc
    hepatitis B core
    HBcAg
    hepatitis B core antigen
    FACS
    fluorescence activated cell sorter
    ELISA
    enzyme linked immunosorbent assay
    PBMC
    peripheral blood mononuclear cells
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