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Research Laboratories
Structural Biology Laboratory
Peter Kwong, Ph.D.

telephone: 301-594-8439
fax: 301-480-2658
e-mail: pdkwong@nih.gov

Address: Vaccine Research Center, NIAID, NIH
40 Convent Drive
Bldg. 40, Room 4508
Bethesda, MD 20892

Group Members (2007):
Priyamvada Acharya, Ph.D.; Lei Chen, Ph.D.; Leo Kong, B.A.; Young Do Kwon, Ph.D.; Shahzad Majeed, M.S.; Gilad Ofek, Ph.D.; Marie Pancera, Ph.D.; Anita Shah, Ph.D.; Jonathan Stuckey; Tongqing Zhou, Ph.D.

Description of Research Program (2007):
The Structural Biology Laboratory 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 the HIV-1 protease inhibitors — current vaccine development makes little use of atomic-level information. We are trying to change this.

HIV-1 generally manages to evade antibody neutralization. Its gp120 glycoprotein (red) has one potential weakness, the site of binding (yellow) for the CD4 receptor. The b12 antibody (green) exploits this weakness - utilizing a functional requirement for rapid association with CD4 - to neutralize HIV-1. This image, from X-ray crystallography, catches the b12 antibody in the act of grabbing onto this site of vulnerability.

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 carbohydrate masquerading as "self" — and also can protect neighboring epitopes through an "evolving glycan shield." We also showed how conformational flexibility of gp120 can combine with quaternary restrictions within the viral spike to prevent antibody neutralization. These and other studies, defining for example protective variable loops, 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. In a collaborative study, we investigated antibodies that bound to the co-receptor-binding site on gp120 and found them capable of neutralizing not only HIV-1, but even the more evolutionary divergent HIV-2. We found such that CD4i antibodies develop to high titers in most HIV-1 infected individuals. Unfortunately, our analysis also found that 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. We are currently exploring how function might constrain the site of CD4 binding, which — unlike the co-receptor-binding site — must be available as an initial site of attachment.

A second line of investigation involves structural analysis of the few broadly neutralizing antibodies that have been identified and that have the ability to neutralize diverse isolates of primary HIV-1. Only four antibodies of such ability have thus far been identified, the antibodies 2F5, 2G12, 4E10, and b12.

We have determined the structures of both 2F5 and also of b12, each with their HIV-1 envelope epitopes. In a collaborative study, primarily with David Baker's group at the University of Washington, Joe Sodroski's group at the Dana-Farber Cancer Institute, and also with Gary Nabel's and Rich Wyatt's groups at the Vaccine Research Center, we are currently generating epitope mimics, unencumbered by known mechanisms of humoral evasion. Tests of these epitope mimics in small animals should reveal their potential to elicit antibodies similar to the template broadly neutralizing ones.

Whether the confluence of structural information that we are generating is sufficient to elicit broadly neutralizing antibodies will depend in part on our ability to iteratively optimize immunogenicity and also on structural parameters of conformational mimicry, epitope accessibility, elicited potency, neutralization breadth, and target specificity. Our investigations have already led to insight into the parameters governing antibody elicitation and neutralization. True success, however, will depend on whether or not we succeed in creating immunogens capable of substantially reducing the incidence of HIV-1 infection in humans.

Links:
Description of Research Program (2001)

Selected publications:

1. Zhou T, Xu L, Dey B, Hessell AJ, Ryk DV, Xiang SH, Yang X, Zhang MY, Zwick MB, Arthos J, Burton DR, Dimitrov DS, Sodroski J, Wyatt R, Nabel GJ, Kwong PD. (2007) Structural definition of a conserved neutralization epitope on HIV-1 gp120. Nature 445, 732-737.
   
   
2. Douek DC, Kwong PD, Nabel GJ. (2006). The rational design of an AIDS vaccine. Cell 124, 677-81.
   
   
3. Huang CC, Tang M, Zhang MY, Majeed S, Montabana E, Stanfield RL, Dimitrov DS, Korber B, Sodroski J, Wilson IA, Wyatt R, Kwong PD. (2005) Structure of a V3-containing HIV-1 gp120 core. Science 310, 1025-8.
   
   
4. Zhou T, Hamer DH, Hendrickson WA, Sattentau QJ, Kwong PD. (2005) Interfacial metal and antibody recognition. Proc Natl Acad Sci U S A 102, 14575-80.
   
   
5. Pancera M, Lebowitz J, Schon A, Zhu P, Freire E, Kwong PD, Roux KH, Sodroski J, Wyatt R. (2005) Soluble mimetics of human immunodeficiency virus type 1 viral spikes produced by replacement of the native trimerization domain with a heterologous trimerization motif: characterization and ligand binding analysis. Journal of Virology 79, 9954-69.
   
   
6. Huang C, Stricher F, Martin L, Decker JM, Majeed S, Barthe P, Hendrickson WA, Robinson J, Roumestand C, Sodroski J, Wyatt R, Shaw GM, Vita C and Kwong PD. (2005) Scorpion-toxin Mimics of CD4 in Complex with Human Immunodeficiency Virus gp120: Crystal Structures, Molecular Mimicry, and Neutralization Breadth. Structure 5, 755-68.
   
   
7. Decker JM, Bibollet-Ruche F, Wei X, Wang S, Levy DN, Wang W, Delaporte E, Peeters M, Derdeyn CA, Allen S, Hunter E, Saag MS, Hoxie JA, Hahn BH, Kwong PD, Robinson JE and Shaw GM. (2005) Antigenic Conservation and Immunogenicity of the HIV Co-Receptor Binding Site. J. Exp. Med. 9, 1407-19.
   
   
8. Kwong PD. (2005) Refolding the Envelope. Nature, 433, 815-816.
   
   
9. Ofek G, Tang M, Sambor A, Katinger H, Mascola JR, Wyatt R and Kwong PD. (2004) Structure and Mechanistic Analysis of the Anti-HIV-1 Antibody 2F5 in Complex with Its gp41 Epitope. Journal of Virology, 78, 10724-10737.
   
   
10. Huang CC, Venturi M, Majeed S, Moore MJ, Phogat S, Zhang MY, Dimitrov DS, Hendrickson WA, Robinson J, Sodroski J, Wyatt R, Choe H, Farzan M, Kwong PD (2004). Structural basis of tyrosine sulfation and VH-gene usage in antibodies that recognize the HIV type 1 coreceptor-binding site on gp120. Proc Natl Acad Sci U S A. 101, 2706-11.
    
    
11. Kwong PD (2004). The 447-52D antibody: hitting HIV-1 where its armor is thickest. Structure 12, 173-4.
    
    
12. Burton DR, Desrosiers RC, Doms RW, Koff WC, Kwong PD, Moore JP, Nabel GJ, Sodroski J, Wilson IA, Wyatt RT (2004). HIV vaccine design and the neutralizing antibody problem. Nat Immunol. 3, 233-6.
    
    
13. Xiang S-H, Wang L, Abreu M, Huang C, Kwong PD, Rosenberg E, Robinson JE and Sodroski J. (2003). Epitope mapping and characterization of a novel CD4-induced human monoclonal antibody capable of neutralizing primary HIV-1 strains. Virology 325, 124-134.
    
    
14. Kock M, Pancera M, Kwong PD, Kolchinsky P, Grundner C, Wang L, Hendrickson WA, Sodroski J and Wyatt R. (2003). Structure-based, Targeted Deglycosylation of HIV-1 gp120 and Effects on Neutralization Sensitivity and Antibody Recognition. Virology 313, 387-400.
    
    
15. Labrijn AF, Poignard P, Raja A, Zwick MB, Delgado K, Franti M, Binley J, Vivona V, Grundner C, Huang CC, Venturi M, Petropoulos CJ, Wrin T, Dimitrov DS, Robinson J, Kwong PD, Wyatt RT, Sodroski J, Burton DR. (2003). Access of Antibody Molecules to the Conserved Coreceptor Binding Site on Glycoprotein gp120 Is Sterically Restricted on Primary Human Immunodeficiency Virus Type 1. J Virol. 77, 10557-10565.
    
    
16. Majeed, S, Ofek G, Belachew A, Huang C, Zhou T and Kwong PD. (2003). Enhancing Protein Crystallization through Precipitant Synergy. Structure 11, 1061-1070.
    
    
17. Choe H, Li W, Wright PL, Vasilieva N, Venturi M, Huang C, Grundner C, Zwick MB, Wang L, Rosenberg ES, Kwong PD, Burton DR, Robinson JE, Sodroski JG and Farzan M. (2003). Tyronsine Sulfation of Human Antibodies Contributes to Recognition of the CCR5 Binding Region of HIV-1 gp120. Cell 114, 161-170.
    
    
18. Wei X, Decker JM, Wang S, Hui H, Kappes JC, Wu X, Salazar-Gonzalez JF, Salazar MG, Kilby JM, Saag MS, Komarova NL, Nowak MA, Hahn BH, Kwong PD, Shaw GM. (2003). Antibody neutralization and escape by HIV-1. Nature 422, 307-312.
    
    
19. Raja A, Venturi M, Kwong P, Sodroski J. (2003). CD4 Binding Site Antibodies Inhibit Human Immunodeficiency Virus gp120 Envelope Glycoprotein Interaction with CCR5. J Virol. 77, 713-718.
    
    
20. Kwong PD, Doyle ML, Casper DJ, Cicala C, Leavitt SA, Majeed S, Steenbeke TD, Venturi M, Chaiken I, Fung M, Katinger H, Parren PW, Robinson J, Van Ryk D, Wang L, Burton DR, Freire E, Wyatt R, Sodroski J, Hendrickson WA, Arthos J. (2002). HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature 420, 678-682.
    
    
21. Xiang SH, Kwong PD, Gupta R, Rizzuto CD, Casper DJ, Wyatt R, Wang L, Hendrickson WA, Doyle ML, Sodroski J. (2002). Mutagenic stabilization and/or disruption of a CD4-bound state reveals distinct conformations of the human immunodeficiency virus type 1 gp120 envelope glycoprotein. J Virol. 76, 9888-9899.
    
    
22. Sanders RW, Venturi M, Schiffner L, Kalyanaraman R, Katinger H, Lloyd KO, Kwong PD, Moore JP. (2002). The mannose-dependent epitope for neutralizing antibody 2G12 on human immunodeficiency virus type 1 glycoprotein gp120. J Virol. 76, 7293-7305.
    
    
23. Yang X, Lee J, Mahony EM, Kwong PD, Wyatt R, Sodroski J. (2002). Highly stable trimers formed by human immunodeficiency virus type 1 envelope glycoproteins fused with the trimeric motif of T4 bacteriophage fibritin. J Virol. 76, 4634-4642.
    
    
24. Kwong, P. D., Wyatt, R., Majeed, S., Robinson, J., Sweet, R. W., Sodroski, J. & Hendrickson, W. A. (2000). Structures of HIV-1 gp120 Envelope Glycoproteins from Laboratory-Adapted and Primary Isolates. Structure 8, 1329-1339.
    
    
25. Myszka, D. G., Sweet, R. W., Hensley, P., Brigham-Burke, M., Kwong, P. D., Hendrickson, W. A., Wyatt, R., Sodroski, J., Doyle, M. L. (2000). Energetics of the HIV gp120-CD4 binding reaction. Proc. Natl. Acad. Sci. USA 97, 9026-9031.
    
    
26. Yang, X., Florin, L., Farzan, M., Kolchinsky, P. Kwong, P. D., Sodroski, J. & Wyatt, R. (2000). Modifications that Stabilize Human Immunodeficiency Virus Envelope Glycoprotein Trimers in Solution. J. Virol. 74, 4746-4754.
    
    
27. Kwong, P. D., Wyatt, R., Sattentau, Q. J., Sodroski, J. & Hendrickson, W. A. (2000). Oligomeric Modeling and Electrostatic Analysis of the gp120 Envelope Glycoprotein of the Human Immunodeficiecy Virus (HIV). J. Virol. 74, 1961-1972.
    
    
28. Moulard, M., Lortat-Jacob, H., Mondor, I., Guillaume, R., Wyatt, R., Sodroski, J., Zhao, L., Olson, W., Kwong, P. D. & Sattentau, Q. J. (2000). Selective Polyanion Interactions with Basic Surfaces on Human Immunodeficiency Virus Type 1 gp120. J. Virol. 74, 1948-1960.
    
    
29. Kwong, P. D., Wyatt, R., Desjardins, E., Robinson, J., Culp, J. S., Hellmig, B. D., Sweet, R. W., Sodroski, J. & Hendrickson, W. A. (1999). Probability Analysis of Variational Crystallization and Its Application to gp120, the Exterior Envelope Glycoprotein of Type 1 Human Immunodeficiency Virus (HIV-1). J. Biol. Chem. 274, 4115-4123.
    
    
30. Kwong, P.D. & Liu, Y. (1999). Use of Cryoprotectants in Combination with Immiscible Oils for Flash-cooling Macromolecular Crystals. J. Applied Crystallography 32, 102-105.
    
    
31. Zhang, W., Canziani, G., Plugariu, C., Wyatt, R., Sodroski, J., Sweet, R. W., Kwong, P. D., Hendrickson, W. A. & Chaiken, I. (1999). Conformational Changes of gp120 in Epitopes near the CCR5 Binding Site are Induced by CD4 and a CD4 Miniprotein Mimetic. Biochemistry 38, 9405-9416.
    
    
32. Binley, J. M., Wyatt, R., Desjardins, E., Kwong, P. D., Hendrickson, W. A., Moore, J. P. & Sodroski, J. (1998). Analysis of the Interaction of Antibodies with a Conserved Enzymatically Deglycosylated Core of the HIV Type 1 Envelope glycoprotein 120. AIDS Research Human Retroviruses 14, 191-198.
    
    
33. Rizzuto, C. D., Wyatt, R., Hernandez-Ramos, N., Sun, Y., Kwong, P. D., Hendrickson, W. A. & Sodroski, J. (1998). A Conserved HIV gp120 Glycoprotein Structure Involved in Chemokine Receptor Binding. Science 280, 1949-1953.
    
    
34. Wyatt, R., Kwong, P. D., Desjardins, E., Sweet, R. W., Robinson, J., Hendrickson, W. A. & Sodroski, J. (1998). The Antigenic Structure of the HIV gp120 Envelope Glycoprotein. Nature 393, 705-711.
    
    
35. Kwong, P.D., Wyatt, R., Robinson, J., Sweet, R. W., Sodroski, J. & Hendrickson, W. A. (1998). Structure of an HIV gp120 Envelope Glycoprotein in Complex with the CD4 Receptor and a Neutralizing Human Antibody. Nature 393, 648-659.