A longitudinal analysis of cytotoxic T lymphocyte precursor frequencies tothe hepatitis B virus in chronically infected patients

Individuals with acute hepatitis B virus (HBV) infection characteristically mount a strong, multispecific cytotoxic T lymphocyte (CTL) response that i s effective in eradicating virus. In contrast, this response in chronic car riers is usually weak or undetectable. Since it is generally acknowledged t hat HBV pathogenesis is immune-mediated, the occurrence of episodes of acti ve liver disease in many carriers suggests that these individuals can mount active CTL responses to HBV. To see whether the detection of circulating C TLs is related to these flare episodes, we have determined the CTL precurso r (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 capsi d (HBc), envelope (HBs) and polymerase (pol) proteins. Assays were performe d against a mixture of peptides, or against each individual peptide, to mea sure overall CTL activity and the multispecificity of the responses, respec tively. Since two of the patients were treated with recombinant human inter leukin-12 (rHuIL-12) at the time, with one individual achieving complete di sease remission a year later after being treated with interferon-alpha, we were also able to examine the effects of these cytokines on HBV cytotoxicit y. Our results indicate that weak but detectable CTL responses do occur in chronic carriers which are generally associated with disease flares, althou gh CTLps were also seen occasionally during minimal disease activity. The r ange of specificities varied between individuals and within each individual during the course of the disease. Finally, we also provide evidence that C TL reactivity is stimulated following treatment with certain cytokines, but is dependent on the time of administration.