Peter Kwong (NIAID National Institute of Health)
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892
Title: Multi-dimensional searching and coordinates of effective vaccines for HIV-1 and RSV
Time: May 12, 11am - 12 pm - see program for more details
Dr. Peter Kwong joined the Dale and Betty Bumpers Vaccine Research Center as chief of the Structural Biology Section in the Laboratory of Virology. Dr. Kwong comes to the Washington area from New York City, where he conducted research in the Department of Biochemistry and Molecular Biophysics at Columbia University. He is joined by the two co-heads of the core, Drs. Cinque Soto and Gwo-Yu Chuang. Dr. Soto received his Ph.D. training under the mentorship of Dr. Barry Honig, Columbia University. Dr. Gwo-Yu Chuang received his Ph.D. training under the mentorship of Dr. Sandor Vajda, Boston University.
A central issue in structural biology is the appropriate way to apply atomic-level information to solve a biological problem. What are the controlling parameters of the biology problem and how can structural biology provide a means to solve it? For example, classical vaccinology fails when confronted with viruses such as human immunodeficiency virus type 1 (HIV-1) or respiratory syncytial virus (RSV). Can the atomic-level tools of structural biology – which provide both access to and manipulation of the chemistry of biological macromolecules – allow for design of effective vaccines against these pathogens? At the Vaccine Center, we have been working to provide an atomic-level understanding of the interaction between the humoral immune response and HIV-1 and RSV. By determining structures of human neutralizing antibodies in complex with their epitopes, we and others are assembling comprehensive summaries of the way the humoral immune system recognizes the fusion glycoproteins of both of these viruses (1,2). We are now delving into the appropriate role structural biology can play in design of effective vaccines. Specifically, an information matrix involving atomic-level design of immunogens, definition of their antigenic and physical properties, solution of key structures, and in vivo feedback on immunogenicity appears to capture the requisite information needed to develop immunogens capable of eliciting protective responses. Informatics derived from this multi-dimensional matrix should, moreover, provide directions for improvement. Examples from RSV will be presented, involving the stabilization of the pre-fusion state with a membrane-distal antigenic target, named antigenic site Ø (zero), on the RSV fusion glycoprotein (1), and implications for application to HIV-1 will be discussed (2,3).
(1) McLellan JS, Chen M, Joyce MG, Sastry M, Stewart-Jones GBE, Yang Y, Zhang B, Chen L, Srivatsan S, Zheng A, Zhou T, Graepel KW, Kumar A, Moin S, Boyington JC, Chuang GY, Soto C, Baxa U, Bakker AQ, Spits A, Beaumont T, Zheng Z, Xia N, Ko SY, Todd JP, Rao S, Graham BS, Kwong PD (2013) Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science 342, 592-598.
(2) Pancera M, Zhou T, Druz A, Georgiev IS, Soto C, Gorman J, Huang J, Acharya P, Chuang GY, Ofek G, Stewart-Jones GBE, Stuckey J, Bailer RT, Joyce MG, Louder MK, Tumba N, Yang Y, Zhang B, Cohen MS, Haynes BF, Mascola JR, Morris L, Munro JB, Blanchard SC, Mothes W, Connors M, Kwong PD (2014) Structure and immune recognition of trimeric prefusion HIV-1 Env. Nature 514, 455-461.
(3) Kwon YD, Pancera M, Acharya P, Georgiev IS, Crooks ET, Gorman J, Joyce , Guttman M, Ma X, Narpala S, Soto C, Terry DS, Yang Y, Zhou T, Ahlsen G, Bailer RT, Chambers M, Chuang GY, Doria-Rose NA, Druz A, Hallen MA, Harned A, Kirys T, Louder MK, O'Dell S, Ofek G, Osawa K, Prabhakaran M, Sastry M, Stewart-Jones GB, Stuckey J, Thomas PV, Tittley T, Williams C, Zhang B, Zhao H, Zhou Z, Donald BR, Lee LK, Zolla-Pazner S, Baxa U, Schön A, Freire E, Shapiro L, Lee KK, Arthos J, Munro JB, Blanchard SC, Mothes W, Binley JM, McDermott AB, Mascola JR, Kwong PD (2015) Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env. Nat Struct Mol Biol 22, 522-531.