Peter D. Kwong, Ph.D.Vaccine Research CenterBuilding 40, Room 450840 Convent DriveBethesda, MD 20892-3027Phone: 301-594-8439Fax: email@example.com
Chief, Structural Biology Section (SBS)Chief, Structural Bioinformatics Core (SBIS)
The Structural Biology Section (SBS) seeks to apply structural biology to the development of an effective HIV-1 vaccine. Despite the enormous potential of atomic-level design—successfully used, for example, in the development of potent drugs against the HIV-1 protease—current vaccine development makes little use of atomic-level information. We are trying to change this.
One area in which we and others have already made an impact is in understanding how HIV-1 is able to evade the humoral immune system. Determination of the structure of the HIV-1 gp120 envelope glycoprotein, the primary target of neutralizing antibodies against HIV-1, showed how N-linked carbohydrate can form both an immunologically silent face—with carbohydrates masquerading as "self"—and also can protect neighboring epitopes through an "evolving glycan shield." Conformational flexibility of gp120 can also combine with quaternary restrictions within the viral spike to prevent antibody neutralization. These and other studies have led to an understanding of the molecular trickery that protects HIV-1 from the humoral immune response.
But can one use structural biology in vaccine design? Currently, we are following two lines of investigation.
One line involves the precise delineation of functional constraints to identify potential footholds of conservation and exposure. Antibodies that bind to the co-receptor binding site on gp120 are capable of recognizing diverse strains of both HIV-1 and also the more evolutionarily divergent HIV-2. Such CD4i antibodies develop to high titers in most HIV-1-infected individuals. Unfortunately, the virus hides the site of co-receptor binding so that—prior to engagement of the primary HIV-1 receptor, CD4—the co-receptor site is not formed. These studies demonstrate the strength of functional constraints in restricting epitope variation, but they also identify an important weakness: Functional conservation does not necessarily engender epitope exposure, which is required for antibody neutralization. A second line of investigation involves structural analysis of human antibodies that have the ability to neutralize diverse isolates of primary HIV-1.
Recently, we put these two lines of investigation together. Unlike the co-receptor- binding site, the initial site of CD4 attachment on the HIV-1 gp120 envelope glycoprotein must be sterically accessible and thus forms a conserved site of vulnerability. By using resurfaced probes specific for this site, we identified natural human antibodies—named VRC01, VRC02, and VRC03—capable of neutralizing over 90 percent of circulating HIV-1 isolates. These antibodies had an unusual feature: extensive changes during the antibody development process of affinity maturation. While typical antibodies have five to ten such changes, VRC01-like antibodies had over 60. We are currently working to understand how the affinity maturation machinery improves the neutralization effectiveness of VRC01-like antibodies. Understanding and controlling this machinery may allow for the elicitation of VRC01-like antibodies and may therefore enable the development of an effective HIV-1 vaccine. One remarkable finding is that antibodies similar to VRC01 have now been identified in almost a dozen HIV-1-infected donors. This reproducibility provides proof-of-principle that potent antibodies similar to VRC01 might be elicited in the general population.
We recently succeeded in using a structure-based approach to develop an effective vaccine against respiratory syncytial virus (RSV), the leading cause of hospitalization for children under five years of age. Our approach focused on a metastable neutralization-sensitive site called antigenic site Ø (zero), at the membrane-distal apex of the RSV fusion (F) glycoprotein. Immunization of mice and non-human primates with a site Ø-stabilized version of RSV F (called DS-Cav1) elicited antibodies many times the protective threshold, thereby validating the structure-based approach. We are now working to apply the insights gleaned from our RSV work to other viral pathogens, including HIV-1.
Dr. Kwong joined the VRC as chief of the Structural Biology Section in the Laboratory of Virology in 2001. 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.
McLellan JS, Chen M, Joyce MG, Sastry M, Stewart-Jones GB, 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 H, Beaumont T, Zheng Z, Xia N, Ko SY, Todd JP, Rao S, Graham BS, Kwong PD. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science. 2013 Nov 1;342(6158):592-8.
Georgiev IS, Doria-Rose NA, Zhou T, Kwon YD, Staupe RP, Moquin S, Chuang GY, Louder MK, Schmidt SD, Altae-Tran HR, Bailer RT, McKee K, Nason M, O'Dell S, Ofek G, Pancera M, Srivatsan S, Shapiro L, Connors M, Migueles SA, Morris L, Nishimura Y, Martin MA, Mascola JR, Kwong PD. Delineating antibody recognition in polyclonal sera from patterns of HIV-1 isolate neutralization. Science. 2013 May 10;340(6133):751-6.
Wu X, Zhou T, Zhu J, Zhang B, Georgiev I, Wang C, Chen X, Longo NS, Louder M, McKee K, O'Dell S, Perfetto S, Schmidt SD, Shi W, Wu L, Yang Y, Yang ZY, Yang Z, Zhang Z, Bonsignori M, Crump JA, Kapiga SH, Sam NE, Haynes BF, Simek M, Burton DR, Koff WC, Doria-Rose NA, Connors M; NISC Comparative Sequencing Program, Mullikin JC, Nabel GJ, Roederer M, Shapiro L, Kwong PD, Mascola JR. Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science. 2011 Sep 16;333(6049):1593-602.
Zhou T, Georgiev I, Wu X, Yang ZY, Dai K, Finzi A, Kwon YD, Scheid JF, Shi W, Xu L, Yang Y, Zhu J, Nussenzweig MC, Sodroski J, Shapiro L, Nabel GJ, Mascola JR, Kwong PD. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science. 2010 Aug 13;329(5993):811-7.
Zhou T, Xu L, Dey B, Hessell AJ, Van Ryk D, Xiang SH, Yang X, Zhang MY, Zwick MB, Arthos J, Burton DR, Dimitrov DS, Sodroski J, Wyatt R, Nabel GJ, Kwong PD. Structural definition of a conserved neutralization epitope on HIV-1 gp120. Nature. 2007 Feb 15;445(7129):732-7.
Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature. 1998 Jun 18;393(6686):648-59.
Visit PubMed for a complete publication listing.
Docked gp120 : CD4 : CCR5Nt (PDB)
Trimeric gp120 : CD4 : HA proportionate (PDB)
Trimeric gp120 : CD4 : IRZJ (PDB)
Visit the RCSB PDB for a more complete listing of SBS structures.
For more information on research conducted by Peter Kwong, Ph.D. visit the Structural Bioinformatics Core Section.
Last Updated January 31, 2014