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Gut. Jul 2000; 47(1): 137–143.
PMCID: PMC1727966
Cytotoxic T lymphocyte responses and CTL epitope escape mutation in HBsAg, anti-HBe positive individuals
S Khakoo, R Ling, I Scott, A Dodi, T Harrison, G Dusheiko, and J Madrigal
Department of Medicine, Royal Free and University College School of Medicine, Royal Free Campus, Pond Street, London NW3 2QG, UK.
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.


Keywords: hepatitis B virus; HLA; hepatitis B core antigen; cytotoxicity; mutant
Figure 1
Figure 1  
Cytotoxicity assay of an individual with acute hepatitis B. (A) Peripheral blood mononuclear cells were stimulated with the HBc/HLA B*0702 dual transfectant and then tested against HBc/B*0702 dual transfectant, vector/B*0702 dual transfectant, (more ...)
Figure 2
Figure 2  
Summary of the cytotoxicity results of the HLA-B7 positive (A), HLA-A2 positive (B), and HLA-A68.1 (C) individuals. Subject No 4 was HBeAg positive, and the remainder were anti-HBe positive, except where indicated. Results are expressed as percentage (more ...)
Figure 3
Figure 3  
Deduced amino acid sequences of the hepatitis B virus (HBV) A68.1 cytotoxic T lymphocyte (CTL) epitope from the HLA-A68.1 positive family compared with that of the HBV adr subtype.26 Numbering is from the start of the core gene and the A68.1 CTL epitope (more ...)
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