title: A longitudinal analysis of cytotoxic T lymphocyte precursor frequencies to the hepatitis B virus in chronically infected patients.
abstract: Individuals with acute hepatitis B virus (HBV) infection characteristically mount a strong, multispecific cytotoxic T lymphocyte (CTL) response that is effective in eradicating virus. In contrast, this response in chronic carriers is usually weak or undetectable. Since it is generally acknowledged that HBV pathogenesis is immune-mediated, the occurrence of episodes of active liver disease in many carriers suggests that these individuals can mount active CTL responses to HBV. To see whether the detection of circulating CTLs is related to these flare episodes, we have determined the CTL precursor (CTLp) frequencies to HLA-A2-restricted viral peptides in seven patients over a 12-24-month period of their disease. Limiting dilution analyses (LDA) were performed longitudinally to five epitopes comprising the viral capsid (HBc), envelope (HBs) and polymerase (pol) proteins. Assays were performed against a mixture of peptides, or against each individual peptide, to measure overall CTL activity and the multispecificity of the responses, respectively. Since two of the patients were treated with recombinant human interleukin-12 (rHuIL-12) at the time, with one individual achieving complete disease remission a year later after being treated with interferon-alpha, we were also able to examine the effects of these cytokines on HBV cytotoxicity. Our results indicate that weak but detectable CTL responses do occur in chronic carriers which are generally associated with disease flares, although CTLps were also seen occasionally during minimal disease activity. The range of specificities varied between individuals and within each individual during the course of the disease. Finally, we also provide evidence that CTL reactivity is stimulated following treatment with certain cytokines, but is dependent on the time of administration.
authors.affiliation: Clinical Research Centre, Royal Brisbane Hospital Research Centre, Herston, Queensland, Australia. garwins@qimr.edu
authors.forename: G K
authors.initials: GK
authors.lastname: Sing
authors.forename: A
authors.initials: A
authors.lastname: Ladhams
authors.forename: S
authors.initials: S
authors.lastname: Arnold
authors.forename: H
authors.initials: H
authors.lastname: Parmar
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Cooper
authors.forename: L
authors.initials: L
authors.lastname: Butterworth
authors.forename: K
authors.initials: K
authors.lastname: Stuart
authors.forename: D
authors.initials: D
authors.lastname: D'Arcy
authors.forename: W G
authors.initials: WG
authors.lastname: Cooksley
mesh_terms: D000328:Adult; D000368:Aged; D004279:DNA, Viral / Q000097:blood; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006512:Hepatitis B Core Antigens / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology* / Q000302:isolation & purification; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D018664:Interleukin-12 / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013997:Time Factors
chemical_list: D004279:DNA, Viral; D018984:Epitopes, T-Lymphocyte; D006512:Hepatitis B Core Antigens; D016898:Interferon-alpha; D011994:Recombinant Proteins; D018664:Interleukin-12