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Cellular immune responses to the hepatitis B virus polymerase
Eishiro Mizukoshi1, John Sidney, Brian Livingston
1Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
Journal of Immunology (Baltimore, Md. : 1950)
|October 21, 2004
Summary
Hepatitis B virus (HBV) polymerase epitopes stimulate immune responses. Long-term antiviral therapy may decrease T cell responses, suggesting combination therapy for a potential therapeutic vaccine.
Area of Science:
- Immunology
- Virology
- Hepatitis B Virus (HBV) Research
Background:
- CD4 T cells are crucial in controlling Hepatitis B virus (HBV) infection through cytokine secretion and by supporting CD8 T cell and B cell responses.
- Understanding T cell epitopes within HBV proteins is vital for analyzing immune responses during infection and treatment.
Purpose of the Study:
- To identify and characterize CD4 T cell epitopes within the HBV polymerase.
- To analyze the immunological effects of long-term antiviral therapy versus spontaneous HBV recovery using these epitopes.
- To explore the potential of these epitopes in developing a therapeutic vaccine for HBV.
Main Methods:
- Identified 10 CD4 T cell epitopes within the HBV polymerase.
- Assessed epitope binding to 14 HLA-DR molecules and T cell responses (IFN-gamma ELISPOT, cytotoxicity assays) in 66 HBV patients and 16 controls.
- Analyzed HBV polymerase-specific T cell responses in acute, chronic, and recovered HBV patients, and during antiviral therapy.
Main Results:
- All 10 identified epitopes bound strongly to prevalent HLA-DR molecules, were conserved, and induced IFN-gamma responses from HBV-specific CD4+ T cells.
- Several epitopes stimulated HBV-specific CD8+ T cell IFN-gamma production and cytotoxicity.
- HBV polymerase-specific T cell responses were significantly higher in patients with acute, self-limited hepatitis and after recovery compared to chronic hepatitis.
- Antiviral therapy initially restored T cell responses but these decreased after 3 years, correlating with lamivudine-resistant mutants and higher HBV titers.
- Reduced T cell responsiveness during prolonged therapy was linked to increased HBV viral load and drug resistance.
Conclusions:
- Newly identified HBV polymerase epitopes are immunogenic and recognized by HBV-specific T cells.
- Long-term antiviral therapy can lead to decreased T cell responsiveness, associated with viral resistance and higher viral loads.
- Combination antiviral and immunostimulatory therapy is warranted, with these HBV polymerase epitopes showing promise for a therapeutic vaccine.