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Interaction of the Hepatitis B Core Antigen and the Innate Immune System¹

Byung O. Lee^*, Amy Tucker^*, Lars Frelin^*, Matti Sallberg, Joyce Jones^*, Cory Peters^*, Janice Hughes^*, David Whitacre^*,, Bryan Darsow^*,, Darrell L. Peterson and David R. Milich^2,*

^* Vaccine Research Institute of San Diego, San Diego, CA 92109; Karolinska Institutet, Clinical Microbiology, Karolinska University Hospital Huddinge, Stockholm, Sweden; VLP Biotech, San Diego, CA 92109; and Virginia Commonwealth University, Department of Biochemistry, Richmond, VA 23298

Previous studies demonstrated that the primary APCs for the hepatitis B core Ag (HBcAg) were B cells and not dendritic cells (DC). We now report that splenic B1a and B1b cells more efficiently present soluble HBcAg to naive CD4⁺ T cells than splenic B2 cells. This was demonstrated by direct HBcAg-biotin-binding studies and by HBcAg-specific T cell activation in vitro in cultures of naive HBcAg-specific T cells and resting B cell subpopulations. The inability of DC to function as APCs for exogenous HBcAg relates to lack of uptake of HBcAg, not to processing or presentation, because HBcAg/anti-HBc immune complexes can be efficiently presented by DC. Furthermore, HBcAg-specific CD4⁺ and CD8⁺ T cell priming with DNA encoding HBcAg does not require B cell APCs. TLR activation, another innate immune response, was also examined. Full-length (HBcAg₁₈₃), truncated (HBcAg₁₄₉), and the nonparticulate HBeAg were screened for TLR stimulation via NF-B activation in HEK293 cells expressing human TLRs. None of the HBc/HBeAgs activated human TLRs. Therefore, the HBc/HBeAg proteins are not ligands for human TLRs. However, the ssRNA contained within HBcAg₁₈₃ does function as a TLR-7 ligand, as demonstrated at the T and B cell levels in TLR-7 knockout mice. Bacterial, yeast, and mammalian ssRNA encapsidated within HBcAg₁₈₃ all function as TLR-7 ligands. These studies indicate that innate immune mechanisms bridge to and enhance the adaptive immune response to HBcAg and have important implications for the use of hepadnavirus core proteins as vaccine carrier platforms.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01 AI049730 and R01 AI20720 and grants from the Swedish Cancer Foundation. L.F. was supported by grants from Erik and Edith Fernströms Foundation and Gålö Foundation/Gemzeús Foundation.

² Address correspondence and reprint requests to Dr. David R. Milich, Vaccine Research Institute of San Diego, 3030 Bunker Hill Street, Suite 300, San Diego, CA 92109.

³ Abbreviations used in this paper: HBV, hepatitis B virus; BMDC, bone marrow-derived dendritic cell; DC, dendritic cell; HS, heparan sulfate; KO, knockout; M, macrophage; Tg, transgenic.