Cellular Immune Responses to the Hepatitis B Virus Polymerase

Abstract

CD4+ T cells play an important role in hepatitis B virus (HBV) infection by secretion of Th1 cytokines that down-regulate HBV replication, and by promoting CD8+ T cell and B cell responses. We have identified and characterized 10 CD4+ T cell epitopes within polymerase and used them to analyze the immunological effects of long-term antiviral therapy as compared with spontaneous recovery from HBV infection. Candidate epitopes were tested for binding to 14 HLA-DR molecules and in IFN-γ ELISPOT and cytotoxicity assays using peripheral blood lymphocytes from 66 HBV-infected patients and 16 uninfected controls. All 10 epitopes bound with high affinity to the most prevalent HLA-DR Ags, were conserved among HBV genomes, and induced IFN-γ responses from HBV-specific CD4+ T cells. Several epitopes contained nested MHC class I motifs and stimulated HBV-specific IFN-γ production and cytotoxicity of CD8+ T cells. HBV polymerase-specific responses were more frequent during acute, self-limited hepatitis and after recovery (12 of 18; 67%) than during chronic hepatitis (16 of 48 (33%); p = 0.02). Antiviral therapy of chronic patients restored HBV polymerase and core-specific T cell responses during the first year of treatment, but thereafter, responses decreased and, after 3 years, were no more frequent than in untreated patients. Decreased T cell responsiveness during prolonged therapy was associated with increased prevalence of lamivudine-resistant HBV mutants and increased HBV titers. The data provide a rationale for the combination of antiviral and immunostimulatory therapy. These newly described HBV polymerase epitopes could be a valuable component of a therapeutic vaccine for a large and ethnically diverse patient population.

Hepatitis B virus DNA is more powerful than HBeAg in predicting peripheral T-lymphocyte subpopulations in chronic HBV-infected individuals with normal liver function tests

“…However, cross-sectional study nature of our data does not allow us to identify the temporal direction of the causal relationship between these two variables. Mizukoshi et al [31] suggested that antiviral therapy of persistently infected patients appeared to increase the frequency of HBV-specific CD4 + T cell responses during the first year of treatment. Boni et al [32][33][34][35] reported that antiviral treatment can overcome CD8 + T cell hypo-responsiveness in subjects with chronic HBV infection, suggesting that the T cells are present, but suppressed.…”

Characterization of Hepatitis B Virus (HBV)-Specific T-Cell Dysfunction in Chronic HBV Infection

“…Because of the very low frequency of tetramer-positive cells in chronic HBV patients, a large number of events (Ͼ1 ϫ 10 6 ) was analyzed by flow cytometry to allow for a reliable phenotypic analysis. Core 18-27, core peptide spanning amino acids 18 to 27; ENV 335-343, envelope peptide spanning amino acids 335 to 343. tural HBV proteins (9,12,13,26,31) and limited information is available about CD4-mediated responses to polymerase (17) and HB x antigen (11) proteins. Here, we used a panel of overlapping 15-mer peptides covering the overall protein sequence of HBV genotype D, which allowed us to detect both CD4-and CD8-mediated responses directed against all structural and nonstructural HBV regions.…”

Lamivudine plus interleukin-12 combination therapy in chronic hepatitis B: Antiviral and immunological activity

“…38,39 The treatment strategy in chronic hepatitis B aims to suppress HBV replication and to restore HBV-specific T-cell responses to achieve sustained remission. Suppression of HBV replication with an antiviral agent can enhance T-cell reactivity to HBV in some patients, 40 but this is transient 41,42 and does not occur in all patients. 43 Therefore, a combination of antiviral and immunomodulatory drugs is likely to be more successful.…”