Structural Studies of the Adaptive and Innate Immune Systems, Viral Pathogens, and Vaccine Design

home11_smallOur major goal is to understand the interaction and neutralization of foreign antigens by the immune system through high-resolution x-ray structural studies of antibodies, Variable Lymphocyte Rectors (VLRs) and antigens in the humoral system, T-cell receptor complexes with MHC class I and class II in the cellular system, and through pattern recognition receptors, such as TLRs, in the innate immune system.

Our Laboratory is focused on immune recognition and, in particular, on how pathogens are recognized and neutralized by the adaptive and innate immune systems. The major goals are to understand the interaction and neutralization of foreign antigens by the immune system through structural studies using mainly high-resolution X-ray. In recent years the lab has integrated other methods such as electron microscope, state of the art biophysical characterization and computational methods into a more integrative approach into understanding the key interactions involved in immune recognition. The information derived from these studies is being used to develop antigens and immunization regiments to illicit broadly neutralizing antibodies against viral pathogens, such as influenza virus and HIV-1.

Much of our recent work is focused on HIV-1 and influenza viruses. The 1918 flu, which killed 20-40 million people worldwide, is being investigated through structural and binding studies of the 1918 viral proteins, such as the hemagglutinin (HA) and neuraminidase, as well as other the viral proteins. The avian H5N1 and swine H1N1 influenza virus HA structures have been determined as well as mutations that enhance binding to human receptors that may allow the virus to cross the species barrier into humans and be transmissible. A very exciting project on broadly neutralizing antibodies with influenza virus has revealed novel epitopes that are of great value for structure-assisted vaccine development.  We have defined a broadly neutralizing epitope in all group 1 influenza subtypes and are working on other antibodies that recognize group 2 as well as those that cross all subtypes. We have also determined structures of almost all of the rare, broadly neutralizing antibodies against the HIV-1 envelope proteins, gp120 and gp41. Recently, in collaboration with the  Weill Cornell Medical College, we have determined the first atomic-level structure of the tripartite HIV envelope protein—long considered one of the most difficult targets in structural biology and of great value for medical science. The new data provide the most detailed picture yet of the AIDS-causing virus’s complex envelope, including sites that future vaccines will try to mimic to elicit a protective immune response. Most of the prior structural studies of this envelope complex focused on individual subunits, but we’ve needed the structure of the full complex to properly define the sites of vulnerability that could be targeted, for example with a vaccine.

    1. Choe J., Kelker M.S., Wilson I.A. (2005) Crystal structure of human toll-like receptor 3 (TLR3) ectodomain. Science 309:581-585.
    2. Stevens J., Blixt O., Tumpey T.M., Taubenberger J.K., Paulson J.C., Wilson I.A. (2006) Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science 312:404-410.
    3. Han, B. W., Herrin, B. R., Cooper, M. D., and Wilson, I. A. (2008) Antigen recognition by variable lymphocyte receptors. Science 321:1834-1837.
    4.  Zajonc, D. M., Striegl, H., Dascher, C. C., and Wilson, I. A. (2008) The crystal structure of avian CD1 reveals a smaller, more primordial antigen-binding pocket compared to mammalian CD1. Proc. Natl. Acad. Sci. U.S.A. 105:17925-17930.
    5.  Xu, R., Ekiert, D. C., Krause, J. C., Hai, R., Crowe, J. E., Jr., and Wilson, I. A. (2010) Structural basis of preexisting immunity to the 2009 H1N1 pandemic influenza virus. Science 328:357-360.
    6. Pejchal, R., Walker, L. M., Stanfield, R. L., Phogat, S. K., Koff, W. C., Poignard, P., Burton, D. R., and Wilson, I. A. (2010) Structure and function of broadly reactive antibody PG16 reveal an H3 subdomain that mediates potent neutralization of HIV-1. Proc. Natl. Acad. Sci. U.S.A. 107:11483-11488.
    7. Yoon, S. I., Hong, M., Han, G. W., and Wilson, I. A. (2010) Crystal structure of soluble MD-1 and its interaction with lipid IVa. Proc. Natl. Acad. Sci. U.S.A. 107:10990-10995.
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    11. Pejchal, R., Doores, K. J., Walker, L. M., Khayat, R., Huang, P. S., et al. (2011) A potent and broad neutralizing antibody recognizes and penetrates the HIV glycan shield. Science 334:1097-1103. PMC ID: 21998254
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    13. Hong, M., Yoon, S. I., and Wilson, I. A. (2012) Structure and functional characterization of the RNA-binding element of the NLRX1 innate immune modulator. Immunity 36:337-347. PMC ID: 22386589
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    15. Ekiert, D.C., Kashyap, A.K., Steel, J., Rubrum, A., Bhabha, G., et al. (2012) Cross-neutralization of influenza A viruses mediated by a single antibody loop. Nature 489:526-532.  PMC ID: 3538848
    16. Moeller, A., Kirchdoerfer, R. N., Potter, C. S., Carragher, B., and Wilson, I. A. (2012) Organization of the influenza virus replication machinery. Science 338:1631-1634. PMC ID: 3578580
    17. Kong, L., Lee, J. H., Doores, K. J., Murin, C. D., Julien, J. P., et al.(2013) Supersite of immune vulnerability on the glycosylated face of HIV-1 envelope glycoprotein gp120. Nat. Struct. Mol. Biol. 20:796-803
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    19. Xu, R., Krause, J. C., McBride, R., Paulson, J. C., Crowe, J. E., Jr., and Wilson, I. A. (2013) A recurring motif for antibody recognition of the receptor-binding site of influenza hemagglutinin. Nat. Struct. Mol. Biol. 20:363-370.
    20. Julien, J.P., Cupo, A., Sok, D., Stanfield, R. L., Lyumkis, D., Deller, M. C., et al. (2013). Crystal Structure of a Soluble Cleaved HIV-1 Envelope Trimer. Science, 342, 1477-1483.
    21. Lyumkis, D., Julien, J.P., de Val, N., Cupo, A., Potter, C. S., Klasse, P. J., et al. (2013). Cryo-EM Structure of a Fully Glycosylated Soluble Cleaved HIV-1 Envelope Trimer. Science, 342, 1484–1490.
    22. Kong, L., Giang, E., Nieusma, T., Kadam, R. U., Cogburn, K. E., Hua, Y., et al. (2013). Hepatitis C virus E2 envelope glycoprotein core structure. Science342, 1090–1094.
    23. Xu, R., de Vries, R. P., Zhu, X., Nycholat, C. M., McBride, R., Yu, W., et al. (2013). Preferential recognition of avian-like receptors in human influenza A H7N9 viruses. Science342(6163), 1230–1235.
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