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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Granger, S.W. & Rickert, S. LIGHT-HVEM signaling and the regulation of T cell–mediated immunity. Cytokine Growth Factor Rev. 14, 289–296 (2003).
Sarrias, M.R. et al. The three HveA receptor ligands, gD, LT-α and LIGHT bind to distinct sites on HveA. Mol. Immunol. 37, 665–673 (2000).
Sedy, J.R. et al. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat. Immunol. 6, 90–98 (2005).
Highlander, S.L. et al. Neutralizing monoclonal antibodies specific for herpes simplex virus glycoprotein D inhibit virus penetration. J. Virol. 61, 3356–3364 (1987).
Montgomery, R.I., Warner, M.S., Lum, B.J. & Spear, P.G. Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell 87, 427–436 (1996).
Connolly, S.A. et al. Structure-based mutagenesis of herpes simplex virus glycoprotein D defines three critical regions at the gD-HveA/HVEM binding interface. J. Virol. 77, 8127–8140 (2003).
Krummenacher, C. et al. Structure of unliganded HSV gD reveals a mechanism for receptor-mediated activation of virus entry. EMBO J. 24, 4144–4153 (2005).
Compaan, D.M. et al. Attenuating lymphocyte activity: the crystal structure of the BTLA-HVEM complex. J. Biol. Chem. 280, 39553–39561 (2005).
Cheung, T.C. et al. Evolutionarily divergent herpesviruses modulate T cell activation by targeting the herpesvirus entry mediator cosignaling pathway. Proc. Natl. Acad. Sci. USA 102, 13218–13223 (2005).
Barber, D.L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006).
Leach, D.R., Krummel, M.F. & Allison, J.P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996).
Schneider, R., Campbell, M., Nasioulas, G., Felber, B.K. & Pavlakis, G.N. Inactivation of the human immunodeficiency virus type 1 inhibitory elements allows Rev-independent expression of Gag and Gag/protease and particle formation. J. Virol. 71, 4892–4903 (1997).
Fitzgerald, J.C. et al. A simian replication-defective adenoviral recombinant vaccine to HIV-1 Gag. J. Immunol. 170, 1416–1422 (2003).
Hensley, S.E., Giles-Davis, W., McCoy, K.C., Weninger, W. & Ertl, H.C. Dendritic cell maturation, but not CD8+ T cell induction, is dependent on type I IFN signaling during vaccination with adenovirus vectors. J. Immunol. 175, 6032–6041 (2005).
Lasaro, M.O., Diniz, M.O., Reyes-Sandoval, A., Ertl, H.C. & Ferreira, L.C. Anti-tumor DNA vaccines based on the expression of human papillomavirus-16 E6/E7 oncoproteins genetically fused with the glycoprotein D from herpes simplex virus-1. Microbes Infect. 7, 1541–1550 (2005).
Lin, K.Y. et al. Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. Cancer Res. 56, 21–26 (1996).
He, Z. et al. Viral recombinant vaccines to the E6 and E7 antigens of HPV-16. Virology 270, 146–161 (2000).
Kresge, K.J. Renewed promise. Annual AIDS vaccine meeting highlights recent data from clinical trials and lessons on recruitment and retention of volunteers. IAVI Rep. 9, 18–20 (2005).
Krieg, C., Boyman, O., Fu, Y.X. & Kaye, J. B and T lymphocyte attenuator regulates CD8+ T cell-intrinsic homeostasis and memory cell generation. Nat. Immunol. 8, 162–171 (2007).
Hurchla, M.A. et al. B and T lymphocyte attenuator exhibits structural and expression polymorphisms and is highly induced in anergic CD4+ T cells. J. Immunol. 174, 3377–3385 (2005).
Han, P., Goularte, O.D., Rufner, K., Wilkinson, B. & Kaye, J. An inhibitory Ig superfamily protein expressed by lymphocytes and APCs is also an early marker of thymocyte positive selection. J. Immunol. 172, 5931–5939 (2004).
Cohen, G.H. et al. Expression of herpes simplex virus type 1 glycoprotein D deletion mutants in mammalian cells. J. Virol. 62, 1932–1940 (1988).
Friedman, H.M., Cohen, G.H., Eisenberg, R.J., Seidel, C.A. & Cines, D.B. Glycoprotein C of herpes simplex virus 1 acts as a receptor for the C3b complement component on infected cells. Nature 309, 633–635 (1984).
Isola, V.J. et al. Fine mapping of antigenic site II of herpes simplex virus glycoprotein D. J. Virol. 63, 2325–2334 (1989).
Whitbeck, J.C. et al. Glycoprotein D of herpes simplex virus (HSV) binds directly to HVEM, a member of the tumor necrosis factor receptor superfamily and a mediator of HSV entry. J. Virol. 71, 6083–6093 (1997).
Bender, F.C. et al. Specific association of glycoprotein B with lipid rafts during herpes simplex virus entry. J. Virol. 77, 9542–9552 (2003).
Carfi, A. et al. Herpes simplex virus glycoprotein D bound to the human receptor HveA. Mol. Cell 8, 169–179 (2001).
Rao, Z. et al. Crystal structure of SIV matrix antigen and implications for virus assembly. Nature 378, 743–747 (1995).
Monaco-Malbet, S. et al. Mutual conformational adaptations in antigen and antibody upon complex formation between an Fab and HIV-1 capsid protein p24. Structure 8, 1069–1077 (2000).
Howard, B.R., Vajdos, F.F., Li, S., Sundquist, W.I. & Hill, C.P. Structural insights into the catalytic mechanism of cyclophilin A. Nat. Struct. Biol. 10, 475–481 (2003).
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.
H.C.E. and M.O.L. have applied for international patent PCT/US2007/018939, “Constructs for Enhancing Immune Responses.”
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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). https://doi.org/10.1038/nm1704
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