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Altered Helper T Lymphocyte Function Associated with Chronic Hepatitis B Virus Infection and its Role in Response to Therapeutic Vaccination in Humans

Brian D. Livingston^1,*, Jeff Alexander^*, Claire Crimi^*, Carla Oseroff^*, Esteban Celis^*, Kieran Daly^*, Luca G. Guidotti, Francis V. Chisari, John Fikes^*, Robert W. Chesnut^* and Alessandro Sette^*

^* Epimmune, San Diego, CA 92121; and Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037

Theradigm-hepatitis B virus (HBV) is an experimental lipopeptide vaccine designed to stimulate induction of HBV-specific CTL responses in HLA-A2 individuals. Previous studies had demonstrated high immunogenicity in healthy volunteers, but comparatively weak CTL responses in chronically infected HBV patients. Herein, we examined helper T lymphocyte (HTL) responses in chronically infected patients. Despite normal proliferation and IL-2 secretion, IL-12 and IFN- secretion in vitro in response to the vaccine was reduced compared with healthy volunteers. A similar pattern of cytokine secretion was observed following mitogen stimulation, suggesting a general altered balance of Th1/Th2 responses. Further analysis indicated that HTL recall responses to whole tetanus toxoid protein were reduced in chronically infected subjects, and reduced responsiveness correlated with the outcome of Theradigm-HBV immunization. Finally, experiments in HBV transgenic mice indicated that the nonnatural Pan DR HTL epitope, PADRE, is capable of inducing high levels of IFN- secretion and that its inclusion in a lipopeptide incorporating an immunodominant L^d-restricted CTL epitope resulted in breaking tolerance at the CTL level. Overall, our results demonstrate an alteration in the quality of HTL responses induced in chronically infected HBV patients and suggest that use of a potent HTL epitope may be important to overcome CTL tolerance against specific HBV Ags.

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