This is an application to develop an entirely new approach to the treatment of chronic HBV infection. Briefly, a combination strategy using the antigen reduction properties of glucosidase inhibitors with an antigen-derived vaccine will be used. Circulating levels of particles containing the viral envelope glycoproteins SHBs (S), MHBs (M) and LHBs (L) characterize chronic HBV infection. The hypothesis that selective reductions in MHBs (and LHBs) antigenemia are sufficient to enhance and complement therapeutic vaccination will be determined. Recent work suggests that animals and people chronically infected with hepadnaviruses possess the potential to mount putative beneficial immunological responses to the virus. It appears that this response can be enhanced or enabled by vaccination using hepadna viral glycoproteins, following reduction of antigenemia with highly effective antiviral agents as demonstrated in the woodchuck model of hepadnavirus infection. We have shown that imino sugar glucosidase inhibitors are effective in selectively reducing the amount of HBV envelope proteins secreted from chronically infected cells in tissue culture as well as, in a much more limited study, woodchucks. Thus glucosidase inhibitors could be ideal complements to vaccine-based therapies by selectively reducing antigen burden. Therefore, the ability of glucosidase inhibitors to selectively reduce HBV envelope antigen levels and enhance the efficacy of antigen based hepatitis vaccines, woodchucks chronically infected with hepadnavirus, will be determined. Tissue culture studies to identify an optimal and appropriate glucosidase inhibitor, and woodchuck studies to determine the feasibility of this approach are proposed. The possibility of an antiviral therapy for eAntigen negative HBV carriers makes this approach all the more compelling.
