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


CONCLUSIONS
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.
Khakoo
S I
SI
Department of Medicine, Royal Free and University College School of Medicine, Royal Free Campus, Pond Street, London NW3 2QG, UK.
Ling
R
R
Scott
I
I
Dodi
A I
AI
Harrison
T J
TJ
Dusheiko
G M
GM
Madrigal
J A
JA
D000328:Adult; D000595:Amino Acid Sequence; D002353:Carrier State / Q000276:immunology; D018929:Cell Culture Techniques; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D005260:Female; D015234:HLA-A Antigens / Q000032:analysis; D006510:Hepatitis B Antibodies / Q000097:blood; D006514:Hepatitis B Surface Antigens / Q000097:blood*; D006513:Hepatitis B e Antigens / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection
D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C053029:HLA-A*68 antigen; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D015395:Histocompatibility Antigens Class I