Khakoo, Salim Iqbal; (1997) Immunological and virological factors in chronic hepatitis B infection. Doctoral thesis (M.D.), University College London.

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Abstract

The work of this thesis is a study of the virological and immunological characteristics of the chronic hepatitis B virus (HBV) carrier state. A study of viral load using a novel signal amplification assay (bDNA, Chiron Corporation, Emeryville, USA) in 71 subjects chronically infected with hepatitis B virus was performed. Seventy five percent of HBeAg positive and 39% of anti-HBe positive carriers were positive using this assay. The assay was more sensitive in the detection of serum HBV DNA than an in-house dot blot assay and more selective for patients requiring anti-viral therapy than nested PCR. In order to subsequently study HLA class I restricted cytotoxic T lymphocyte (CTL) responses in the peripheral blood of HBV infected patients, a panel of dual transfectant target cell lines, derived from the L721.221 HLA-A, -B, -C null line was created which express a single HLA class I allele and the hepatitis B nucleocapsid antigen. These were used in a series of cytotoxicity assays and CTL responses demonstrated in one out of five HLA-A2 positive, three out of five HLA-B7 positive and one out two HLA-B35 positive carriers. In three out of three HLA-A2, -B7 positive individuals responses were only detected in the context of HLA-B7 and not HLA-A2, suggesting preferential recognition of the nucleocapsid antigen in the context of HLA-B7. In a family of HLA-A68 positive chronic HBV carriers, CTL responses were detected in one out of three patients tested. Sequencing of the HBc141-151 HLA-A68 restricted CTL epitope in the virions of the family members demonstrated the presence of an arginine to cysteine substitution at the amino-terminus of the peptide in four of the anti-HBe positive affected siblings, but not the HBeAg positive carrier. These data suggest that CTL responses are demonstrable in the peripheral blood of chronic HBV carriers, and that mutation in a CTL epitope is likely to be a consequence of this reactivity.

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