Targeting of antigen to the herpesvirus entry mediator augments primary adaptive immune responses

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Abstract

Interactions between the herpesvirus entry mediator (HVEM) and the B- and T-lymphocyte attenuator (BTLA) inhibit B and T cell activation. HVEM-BTLA interactions are blocked by herpes simplex virus (HSV) glycoprotein D (gD) through binding of its N-terminal domain to the BTLA binding site of HVEM. In this study, we inserted viral antigens into the C-terminal domain of gD and expressed these antigens with plasmid or E1-deleted (replication-defective) adenovirus vectors. Viral antigens fused to gD induced T and B cell responses to the antigen that were far more potent than those elicited by the same antigen expressed without gD. The immunopotentiating effect required binding of the gD chimeric protein to HVEM. Overall, the studies demonstrate that targeting of antigen to the BTLA binding site of HVEM augments the immunogenicity of vaccines.

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Figure 1: gD chimeric proteins bind HVEM.
Figure 2: CD8+ T cell responses to vectors expressing antigens fused to gD.
Figure 3: Phenotypes of Gag-specific CD8+ T cells were analyzed in PBMCs from mice immunized with either AdC68gD-Gag or AdC68Gag.
Figure 4: CD8+ T cells induced by gD chimeric protein are functional in vivo.

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Acknowledgements

This work was sponsored by a US National Institutes of Health grant (AI-052271) to H.C.E.; a US National Institute of Allergy and Infectious Diseases grant (AI-18289) to J.C.W., G.H.C. and R.J.E.; and institutional grants to the Wistar Institute including a US National Cancer Institute Cancer Core Grant (CA10815) and the Commonwealth Universal Research Enhancement Program from the Pennsylvania Department of Health. M.O.L. was supported with a fellowship from the Cancer Research and Prevention Foundation. We thank the MHC Tetramer Core Facility (Emory University Vaccine Center, Atlanta, Georgia) for providing the Gag-tetramer, T.C. Wu (Johns Hopkins University, Baltimore, Maryland) for providing TC-1 cells, K. High and S. Murphy (University of Pennsylvania, Philadelphia, Pennsylvania) for human PBMC RNA samples, W. Giles-Davis for excellent technical assistance, J. Faust and M. Farabaugh for assistance with flow cytometry, J. Hayden and F. Keeney for assistance with confocal microscopy, and C. Cole and C. Barth for preparation of the manuscript.

Author information

M.O.L. planned and performed most of the experiments and wrote the manuscript; N.T. and S.E.H. planned some experiments and contributed to writing of the manuscript; J.C.W. and S.-W.L. planned and performed some of the experiments; J.J.R. performed the molecular modeling; E.J.W. provided technical advice; G.H.C. and R.J.E. provided advice; and H.C.E. supervised all experimental procedures and helped to write the manuscript.

Correspondence to Hildegund C Ertl.

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Competing interests

H.C.E. and M.O.L. have applied for international patent PCT/US2007/018939, “Constructs for Enhancing Immune Responses.”

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Supplementary Figs. 1–5 and Supplementary Tables 1 & 2 (PDF 1048 kb)

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Lasaro, M., Tatsis, N., Hensley, S. et al. Targeting of antigen to the herpesvirus entry mediator augments primary adaptive immune responses. Nat Med 14, 205–212 (2008) doi:10.1038/nm1704

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