Peter D. Kwong, Ph.D.
Structural Biology Section
Description of Research Program
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 potent drugs against the HIV-1 protease—current vaccine development makes little use of atomic-level information. We are trying to change this.
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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 (NIH news release).
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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" (1,2,18). We also showed how conformational flexibility of gp120 can combine with quaternary restrictions within the viral spike to prevent antibody neutralization (16). 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. Antibodies that bind to the co-receptor binding site on gp120 are capable of recognizing diverse strains of not only HIV-1, but also the more evolutionarily divergent HIV-2 (29). 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 (21).
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 the few monoclonal antibodies that 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 (32). By using resurfaced probes specific for this site, we identified natural human antibodies—named VRC01, VRC02 and VRC03—capable of neutralizing over 90% of circulating HIV-1 isolates (60, 61). These antibodies had an unusual feature, extensive changes during the antibody development process of affinity maturation; while typical antibodies have 5-10 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 should allow for the elicitation of VRC01-like antibodies, and may therefore enable the development of an effective HIV-1 vaccine.
Structural Biology Section 2011
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Left to Right:
Top row: Tao Wang, Mallika Sastry, Adi Ofek,
2nd row: Jennifer Burke, Jonathan Stuckey, Lei Chen,
3rd row: Marie Pancera, Jeffrey Boyington, Jason McLellan, Stephanie Moquin, Peter Kwong,
4th row: Priyamvada Acharya, Baoshan Zhang, Timothy Luongo, Jason Gorman, Tongqing Zhou, Syed Hussan,
5th row: Yongping Yang, Gordon Joyce, Young Do Kwon |
Links
Description of Research Program (2001)
Selected Publications
94. Lalonde JM, Kwon YD, Jones DM, Sun AW, Courter JR, Soeta T, Kobayashi T, Princiotto AM, Xueling W, Schön A, Freire E, Kwong PD, Mascola JR, Sodroski JG, Madani N, Smith AB (2012). Structure-Based Design, Synthesis and Characterization of Dual Hotspot Small-Molecule HIV-1 Entry Inhibitors.
J Med Chem. [Epub April 12th].
93. Kwon YD, Finzi A, Wu X, Dogo-Isonagie C, Lee LK, Moore LR, Schmidt SD, Stuckey J, Yang Y, Zhou T, Zhu J, Vicic DA, Debnath AK, Shapiro L, Bewley CA, Mascola JR, Sodroski JG, Kwong PD (2012). Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops. Proc Natl Acad Sci. (Epub Mar 26th). PDB: 3TGQ, 3TGR, 3TGS, 3TGT, 3TIH.
92. Dogo-Isonagie C, Lam S, Gustchina E, Acharya P, Yang Y, Shahzad-Ul-Hussan S, Clore GM, Kwong PD, Bewley CA (2012). Peptides from the second extracellular loop of the C-C chemokine receptor type 5 (CCR5) inhibit diverse strains of HIV-1. J Biol Chem. (Epub Mar 8th).
91. Falkowska E, Ramos A, Feng Y, Zhou T, Moquin S, Walker LM, Wu X, Seaman MS, Wrin T, Kwong PD, Wyatt RT, Mascola JR, Poignard P, Burton DR (2012). PGV04, an HIV-1 gp120 CD4 Binding Site Antibody, Is Broad and Potent in Neutralization but Does Not Induce Conformational Changes Characteristic of CD4. J Virol. 86, 4394-403 (Epub Feb 15th).
90. Bonsignori M, Montefiori DC, Wu X, Chen X, Hwang KK, Tsao CY, Kozink DM, Parks RJ, Tomaras GD, Crump JA, Kapiga SH, Sam NE, Kwong PD, Kepler TB, Liao HX, Mascola JR, Haynes BF (2012). Two Distinct Broadly Neutralizing Antibody Specificities of Different Clonal Lineages in a Single HIV-1-Infected Donor: Implications for Vaccine Design. J Virol. 86, 4688-92 (Epub Feb 1st).
89. Hansman GS, Taylor DW, McLellan JS, Smith TJ, Georgiev I, Tame JR, Park SY, Yamazaki M, Gondaira F, Miki M, Katayama K, Murata K, Kwong PD (2012). Structural Basis for Broad Detection of Genogroup II Noroviruses by a Monoclonal Antibody That Binds to a Site Occluded in the Viral Particle. J Virol. 86, 3635-46 (Epub Jan 25th). PDB: 3V7A. EMDataBank: EMD-5374.
88. Kwong PD, Mascola JR, Nabel GJ (2012). Structural Biology and Other Resolution-Enhancing Technologies in the Design of an Effective HIV–1 Vaccine. NIH Publication 11-7778, 40.
87. Kwong PD, Mascola JR, Nabel GJ (2011). Rational Design of Vaccines to Elicit Broadly Neutralizing Antibodies to HIV-1. Cold Spring Harb Perspect Med. 1, a007278.
86. Dennison SM, Sutherland LL, Jaeger FH, Anasti KM, Parks R, Stewart S, Bowman C, Xia SM, Zhang R, Shen X, Scearce RM, Ofek G, Yang Y, Kwong PD, Santra S, Liao HX, Tomaras G, Letvin NL, Chen B, Alam SM, Haynes BF (2011). Induction of Antibodies in Rhesus Macaques That Recognize a Fusion-Intermediate Conformation of HIV-1 gp41. PLoS One 6, e27824 (Epub Nov 30th).
85. McLellan JS, Pancera M, Carrico C, Gorman J, Julien JP, Khayat R, Louder R, Pejchal R, Sastry M, Dai K, O'Dell S, Patel N, Shahzad-Ul-Hussan S, Yang Y, Zhang B, Zhou T, Zhu J, Boyington JC, Chuang GY, Diwanji D, Georgiev I, Do Kwon Y, Lee D, Louder MK, Moquin S, Schmidt SD, Yang ZY, Bonsignori M, Crump JA, Kapiga SH, Sam NE, Haynes BF, Burton DR, Koff WC, Walker LM, Phogat S, Wyatt R, Orwenyo J, Wang LX, Arthos J, Bewley CA, Mascola JR, Nabel GJ, Schief WR, Ward AB, Wilson IA, Kwong PD (2011). Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature. 480, 336-43 (Epub Nov 23rd). PDB: 3U1S, 3U2S, 3U36, 3U46, 3U4B, 3U4E, 3TCL.
84. Kong R, Li H, Bibollet-Ruche F, Decker JM, Zheng NN, Gottlieb GS, Kiviat NB, Salif Sow P, Georgiev I, Hahn BH, Kwong PD, Robinson JE, Shaw GM (2011). Broad and Potent Neutralizing Antibody Responses Elicited in Natural HIV-2 Infection. J Virol. 86, 947-60 (Epub Oct 26th).
83. Hansman GS, Shahzad-Ul-Hussan S, McLellan JS, Chuang GY, Georgiev I, Shimoike T, Katayama K, Bewley CA, Kwong PD (2011). Structural basis for norovirus inhibition and fucose mimicry by citrate. J Virol. 86, 284-92 (Epub Oct 26th). PDB: 3RY8.
82. Azoitei ML, Correia BE, Ban YE, Carrico C, Kalyuzhniy O, Chen L, Schroeter A, Huang PS, McLellan JS, Kwong PD, Baker D, Strong RK, Schief WR (2011). Computation-guided backbone grafting of a discontinuous motif onto a protein scaffold. Science. 334, 373-6. PDB: 3RPT, 3RU8.
81. Kim M, Sun ZY, Rand KD, Shi X, Song L, Cheng Y, Fahmy AF, Majumdar S, Ofek G, Yang Y, Kwong PD, Wang JH, Engen JR, Wagner G, Reinherz EL (2011). Antibody mechanics on a membrane-bound HIV segment essential for GP41-targeted viral neutralization. Nat Struct Mol Biol. 18, 1235-43.
80. Nabel GJ, Kwong PD, Mascola JR (2011). Progress in the rational design of an AIDS vaccine. Philos Trans R Soc Lond B Biol Sci. 366, 2759-65.
79. Zhu Z, Qin HR, Chen W, Zhao Q, Shen X, Schutte R, Wang Y, Ofek G, Streaker E, Prabakaran P, Fouda GG, Liao HX, Owens J, Louder M, Yang Y, Klaric KA, Moody MA, Mascola JR, Scott JK, Kwong PD, Montefiori D, Haynes BF, Tomaras GD, Dimitrov DS (2011). Cross-reactive HIV-1-neutralizing human monoclonal antibodies identified from a patient with 2F5-like antibodies. J Virol. 85, 11401-8 (Epub Aug 31st).
78. 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 (2011). Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science. 333, 1593-602 (Epub Aug 11th). PDB: 3SE8, 3SE9.
77. Bonsignori M, Hwang KK, Chen X, Tsao CY, Morris L, Gray E, Marshall DJ, Crump JA, Kapiga SH, Sam NE, Sinangil F, Pancera M, Yongping Y, Zhang B, Zhu J, Kwong PD, O'Dell S, Mascola JR, Wu L, Nabel GJ, Phogat S, Seaman MS, Whitesides JF, Moody MA, Kelsoe G, Yang X, Sodroski J, Shaw GM, Montefiori DC, Kepler TB, Tomaras GD, Alam SM, Liao HX, Haynes BF (2011). Analysis of a clonal lineage of HIV-1 envelope V2/V3 conformational epitope-specific broadly neutralizing antibodies and their inferred unmutated common ancestors. J Virol. 85, 9998-10009 (Epub Jul 27th).
76. Acharya P, Dogo-Isonagie C, LaLonde JM, Lam SN, Leslie GJ, Louder MK, Frye LL, Debnath AK, Greenwood JR, Luongo TS, Martin L, Watts KS, Hoxie JA, Mascola JR, Bewley CA, Kwong PD (2011). Structure-based identification and neutralization mechanism of tyrosine sulfate mimetics that inhibit HIV-1 entry. ACS Chem Biol. 6, 1069-77 (Epub Aug 5th).
75. Kwong PD, Shapiro L (2011). Vaccine design reaches the atomic level. Sci Transl Med. 3, 91ps29.
74. Sastry M, Xu L, Georgiev IS, Bewley CA, Nabel GJ, Kwong PD (2011). Mammalian production of an isotopically enriched outer domain of the HIV-1 gp120 glycoprotein for NMR spectroscopy. J Biomol NMR 50, 197-207 (Epub Jun 12th).
73. McLellan JS, Yang Y, Graham BS, Kwong PD (2011). Structure of respiratory syncytial virus fusion glycoprotein in the postfusion conformation reveals preservation of neutralizing epitopes. J Virol. 85, 7788-96 (Epub May 25th). PDB: 3RRR, 3RRT.
72. McLellan JS, Correia BE, Chen M, Yang Y, Graham BS, Schief WR, Kwong PD (2011). Design and characterization of epitope-scaffold immunogens that present the motavizumab epitope from respiratory syncytial virus. J Mol Biol. 409, 853-66 (Epub Apr 27th). PDB: 3QWO.
71. Hansman GS, Biertümpfel C, Georgiev I, McLellan JS, Chen L, Zhou T, Katayama K, Kwong PD (2011). Crystal Structures of GII.10 and GII.12 Norovirus Protruding Domains in Complex with Histo-Blood Group Antigens Reveal Details for a Potential Site of Vulnerability. J Virol. 85, 6687-701 (Epub Apr 27th). PDB: 3ONU, 3ONY, 3PA1, 3PA2, 3Q38, 3Q39, 3Q3A, 3Q6Q, 3Q6R, 3R6J, 3R6K.
70. Wu X, Changela A, O'Dell S, Schmidt SD, Pancera M, Yang Y, Zhang B, Gorny MK, Phogat S, Robinson JE, Stamatatos L, Zolla-Pazner S, Kwong PD, Mascola JR (2011). Immunotypes of a quaternary site of HIV-1 vulnerability and their recognition by antibodies. J Virol. 85, 4578-85 (Epub Feb 16th).
69. Guenaga J, Dosenovic P, Ofek G, Baker D, Schief WR, Kwong PD, Karlsson Hedestam GB, Wyatt RT (2011). Heterologous epitope-scaffold prime:boosting immuno-focuses B cell responses to the HIV-1 gp41 2F5 neutralization determinant. PLoS One 6, e16074.
68. Changela A, Wu X, Yang Y, Zhang B, Zhu J, Nardone GA, O’Dell S, Pancera M, Gorny MK, Phogat S, Robinson JE, Stamatatos L, Zolla-Pazner S, Mascola JR, Kwong PD (2011). Crystal structure of human antibody 2909 reveals conserved features of quaternary-specific antibodies that potently neutralize HIV-1. J Virol. 85, 2524-35 (Epub 2010 Dec 29th). PDB: 3piq.
67. LaLonde, J. M., Elban, M. A., Courter, J. R., Sugawara, A., Soeta, T., Mandani, N., Princiotto, A. M., Kwon, Y. D., Kwong, P. D., Freire, E., Sodroski, J., and Smith, A. B. 3rd. (2011). Design, synthesis and biological evaluation of small molecule inhibitors of CD4-gp120 binding based on virtual screening. Bioorg & Med. Chem. 19, 91-101 (Epub 2010 Nov 26th).
66. McLellan, J. S., Chen, M., Chang, J. S., Yang, Y., Kim, A., Graham, B. S., and Kwong, P.D. (2010). Structure of a Major Antigenic Site on the Respiratory Syncytial Virus Fusion Glycoprotein in Complex with Neutralizing Antibody 101F. J Virol. 84, 12236-12244 (Epub Sep 29). PDB: 3o41, 3o45.
65. Ofek, G., Guenaga, F. J., Schief, W. R., Skinner, J., Baker, D., Wyatt, R., and Kwong, P. D. (2010). Feature Article: From the Cover: Elicitation of structure-specific antibodies by epitope scaffolds. Proc Natl Acad Sci. 107, 17880-87. PDB: 3les, 3lev, 3lex, 3ley.
64. Kong, L., Sheppard, N. C., Stewart-Jones, G. B., Robson, C. L., Chen, H., Xu, X., Krashias, G., Bonomelli, C., Scanlan, C. N., Kwong, P. D., Jeffs, S. A., Jones, I. M., and Sattentau, Q. J. (2010). Expression-system-dependent modulation of HIV-1 envelope glycoprotein antigenicity and immunogenicity. J Mol Biol. 403, 131-47.
63. Kong, L., Huang, C. C., Coales, S. J., Molnar, K. S., Skinner, J., Hamuro, Y., and Kwong, P. D. (2010). Local conformational stability of HIV-1 gp120 in unliganded and CD4-bound states as defined by amide hydrogen/deuterium exchange. J Virol. 84, 10311-10321.
62. Kwong, P. D., Nabel, G. J., Acharya, P., Boyington, J. C., Hood, C., Chen, L., Kim, A., Kong L., Kwon, Y. D., Majeed, S., McLellan, J., Ofek, G., Pancera, M., Sastry, M., Shah, A. C., Stuckey, J., and Zhou, T. (2010). Structural Biology and the Design of Effective Vaccines for HIV-1 and Other Viruses.
In “National Institute of Allergy and Infectious Disease, NIH, Volume 3: Intramural Research” (Editor Vassil St. Georgiev, Humana Press).
61. Zhou, T., Georgiev, I., Wu, X., Yang, Z., Dai, K., Finzi, A., Kwon, Y. D., Scheid, J., Shi, W., Xu, L., Yang, Y., Zhu, J., Nussenzweig, M. C., Sodroski, J., Shapiro, L., Nabel, G. J., Mascola, J. R., and Kwong, P. D. (2010). Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01. Science 329 (5993), 811-817 (Epub July 8). PDB: 3ngb.
60. Wu, X., Yang, Z., Li, Y., Hogerkorp, C., Schief, W. R., Seaman, M. S., Zhou, T., Schmidt, S. D., Wu, L., Xu, L., Longo, N. S., McKee, K., O’Dell, S., Louder, M. K., Wycuff, D. L., Feng, Y., Nason, M., Doria-Rose, N., Connors, M., Kwong, P. D., Roederer, M., Wyatt, R. T., Nabel, G. J., and Mascola, J. R. (2010). Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1. Science 329 (5993), 856-861 (Epub July 8).
59. Pancera, M., McLellan, J. S., Wu, X., Zhu, J., Changela, A., Schmidt, S. D., Yang, Y., Zhou, T., Phogat, S., Mascola, J. R., and Kwong, P. D. (2010). Crystal structure of PG16 and chimeric dissection with somatically related PG9: Structure-function analysis of two quaternary-specific antibodies that effectively neutralize HIV-1. J Virol. 84, 8098-8110 (Epub June 10). PDB: 3lrs, 3mme.
58. Finzi, A., Pacheco, B., Zeng, X., Kwon, Y. D., Kwong, P. D., and Sodroski, J. (2010). Conformational characterization of aberrant disulfide-linked HIV-1 gp120 dimers secreted from overexpressing cells. J Virol Methods. 168, 155-161 (Epub May 13).
57. Finzi, A., Xiang, S. H., Pacheco, B., Wang, L., Haight, J., Kassa, A., Danek, B., Pancera, M., Kwong, P. D., and Sodroski, J. (2010). Topological Layers in the HIV-1 gp120 Inner Domain Regulate gp41 Interaction and CD4-Triggered Conformational Transitions. Mol. Cell. 37 656-67.
56. Xiang, S. H., Finzi, A., Pacheco, B., Alexander, K., Yuan, W., Rizzuto, C., Huang, C. C., Kwong, P. D., and Sodroski, J. (2010). A V3 Loop-Dependent gp120 Element Disrupted by CD4 Binding Stabilizes the Human Immunodeficiency Virus (HIV-1) Envelope Glycoprotein Trimer. J Virol. 84, 3147-61.
55. Hood, C. L., Abraham, J., Boyington, J. C., Leung, K., Kwong, P. D., and Nabel, G. J. (2010). Biochemical and structural characterization of Cathepsin L-processed Ebola virus glycoprotein: implications for viral entry and immunogenicity. J Virol. 84, 2972-82.
54. Ofek, G., McKee, K., Yang, Y., Yang, Z. Y., Skinner, J., Guenaga, F. J., Wyatt, R., Zwick, M. B., Nabel, G. J., Mascola, J. R., and Kwong, P. D. (2010). Relationship between Antibody 2F5 Neutralization of HIV-1 and Hydrophobicity of Its Heavy Chain Third Complementarity-Determining Region. J Virol. 84, 2955-62.
53. McLellan, J. S., Chen, M., Kim, A., Yang, Y., Graham, B. S., and Kwong, P. D. (2010). Structural basis of respiratory syncytial virus neutralization by motavizumab. Nat Struct Mol Biol. 248-250. PDB: 3ixt.
52. Pancera, M., Majeed, S., Ban, Y. E., Chen, L., Huang, C. C., Kong, L., Kwon, Y. D., Stuckey, J., Zhou, T., Robinson, J. E., Schief, W. R., Sodroski, J., Wyatt, R., and Kwong, P. D. (2010). Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility. Proc Natl Acad Sci. 107, 1166-71. PDB: 3jwd, 3jwo.
51. Chen, L., Kwon, Y. D., Zhou, T., Wu, X., O'Dell, S., Cavacini, L., Hessell, A. J., Pancera, M., Tang, M., Xu, L., Yang, Z. Y., Zhang, M. Y., Arthos, J., Burton, D. R., Dimitrov, D. S., Nabel, G. J., Posner, M. R., Sodroski, J., Wyatt, R., Mascola, J. R., and Kwong, P. D. (2009). Structural basis of immune evasion at the site of CD4 attachment on HIV-1 gp120. Science. 326, 1123-7. PDB: 3hi1, 3idx, 3idy.
50. Wu, X., Zhou, T., O'Dell, S., Wyatt, R. T., Kwong, P. D., and Mascola, J. R. (2009). Mechanism of human immunodeficiency virus type 1 resistance to monoclonal antibody B12 that effectively targets the site of CD4 attachment. J Virol. 83, 10892-907.
49. Kwong, P. D., Mascola, J. R., and Nabel, G. J. (2009). Mining the B cell repertoire for broadly neutralizing monoclonal antibodies to HIV-1. Cell Host Microbe. 6, 292-4.
48. Kassa, A., Madani, N., Schön, A., Haim, H., Finzi, A., Xiang, S. H., Wang, L., Princiotto, A., Pancera, M., Courter, J., Smith, A. B. 3rd, Freire, E., Kwong, P. D., and Sodroski, J. (2009). Transitions to and from the CD4-bound conformation are modulated by a single-residue change in the human immunodeficiency virus type 1 gp120 inner domain. J Virol. 83, 8364-78.
47. Kwong, P. D., and Wilson, I. A. (2009). HIV-1 and influenza antibodies: seeing antigens in new ways. Nat Immunol. 10, 573-8.
46. Dey, B., Svehla, K., Xu, L., Wycuff, D., Zhou, T., Voss, G., Phogat, A., Chakrabarti, B. K., Li, Y., Shaw, G., Kwong, P. D., Nabel, G. J., Mascola, J. R., and Wyatt, R. T. (2009). Structure-based stabilization of HIV-1 gp120 enhances humoral immune responses to the induced co-receptor binding site. PLoS Pathog. 5, e1000445.
45. Wu, L., Zhou, T., Yang, Z. Y., Svehla, K., O'Dell, S., Louder, M. K., Xu, L., Mascola, J. R., Burton, D. R., Hoxie, J. A., Doms, R. W., Kwong, P. D., and Nabel, G. J. (2009). Enhanced exposure of the CD4-binding site to neutralizing antibodies by structural design of a membrane-anchored human immunodeficiency virus type 1 gp120 domain. J Virol. 83, 5077-86.
44. Davis, K. L., Bibollet-Ruche, F., Li, H., Decker, J. M., Kutsch, O., Morris, L., Salomon, A., Pinter, A., Hoxie, J. A., Hahn, B. H., Kwong, P. D., and Shaw, G. M. (2009). Human Immunodeficiency Virus Type 2 (HIV-2)/HIV-1 Envelope Chimeras Detect High Titers of Broadly Reactive HIV-1 V3-Specific Antibodies in Human Plasma. J Virol. 83, 1240-1259.
43. Mörner, A., Douagi, I., Forsell, M. N., Sundling, C., Dosenovic, P., O'Dell, S., Dey, B., Kwong, P. D., Voss, G., Thorstensson, R., Mascola, J. R., Wyatt, R. T., and Karlsson Hedestam, G. B. (2009). Human immunodeficiency virus type 1 env trimer immunization of macaques and impact of priming with viral vector or stabilized core protein. J Virol. 83, 540-551.
42. Lam, S. N., Acharya, P., Wyatt, R., Kwong, P. D., and Bewley, C. A. (2008). Tyrosine-sulfate isosteres of CCR5 N-terminus as tools for studying HIV-1 entry. Bioorg Med Chem. 16, 10113–10120.
41. Madani, N., Schön, A., Princiotto, A. M., Lalonde, J. M., Courter, J. R., Soeta, T., Ng, D., Wang, L., Brower, E. T., Xiang, S. H., Kwon, Y. D., Huang, C. C., Wyatt, R., Kwong, P. D., Freire, E., Smith, A. B. 3rd, and Sodroski, J. (2008). Small-molecule CD4 mimics interact with a highly conserved pocket on HIV-1 gp120. Structure 1689-1701.
40. Stricher, F., Huang, C. C., Descours, A., Duquesnoy, S., Combes, O., Decker, J. M., Kwon, Y. D., Lusso, P., Shaw, G. M., Vita, C., Kwong, P. D., and Martin, L. (2008). Combinatorial optimization of a CD4-mimetic miniprotein and cocrystal structures with HIV-1 gp120 envelope glycoprotein. J Mol Biol. 382, 510-524. PDB: 2i5y, 2i60.
39. Huang, C., Lam, S., Acharya, P., Tang, M., Xiang, S. H., Shahzad-ul-Hussan, S., Stanfield, R.L., Robinson, J., Sodroski, J., Wilson, I. A., Wyatt, R., Bewley, C. A., and Kwong, P. D. (2007). Structures of the CCR5 N-terminus and of a tyrosine-sulfated antibody with HIV-1 gp120 and CD4. Science. 317, 1930-1934. PDB: 2rll, 2qad, CCR5Nt-docked (Zip).
38. Xie, H., Ng, D., Savinov, S. N., Dey, B., Kwong, P.D., Wyatt, R., Smith III, A. B., and Hendrickson, W. A. (2007). Structure-activity relations in the binding of chemically derived CD4 to human immunodeficiency virus gp120. J. Med. Chem. 50, 4898-4908.
37. Lin, G., Bertolotti-Ciarlet, A., Haggarty, B., Romano, J., McGeehan, K., Leslie, G., Polichiani d’Oliviere, A., Huang, C., Kwong, P. D., Doms, R. W., and Hoxie, J. A. (2007). Replication competent variants of human immunodeficiency virus type 2 lacking the V3 loop exhibit resistance to chemokine receptor antagonists. J Virol. 81, 9956-9966.
36. Dey, B., Pancera, M., Svehla, K., Shu, Y., Xiang, S. H., Vainshtein, J., Li, Y., Sodroski, J., Kwong, P. D., Mascola, J. R., and Wyatt, R. (2007). Characterization of human immunodeficiency virus type 1 monomeric and trimeric gp120 glycoproteins stabilized in the CD4-bound state: Antigenicity, biophysics, and immunogenicity. J Virol. 81, 5579-5593.
35. Zhou, T., Xu, L., Dey, B., Hessell, A. J., Ryk, D. V., Xiang, S. H., Yang, X., Zhang, M. Y., Zwick, M. B., Arthos, J., Burton, D. R., Dimitrov, D. S., Sodroski, J., Wyatt, R., Nabel, G. J., and Kwong, P. D. (2007). Structural definition of a conserved neutralization epitope on HIV-1 gp120. Nature. 445, 732-737. PDB: 2nxy, 2nxz, 2ny0, 2ny1, 2ny2, 2ny3, 2ny4, 2ny5, 2ny6, 2ny7.
34. Douek, D. C., Kwong, P. D., and Nabel, G. J. (2006). The rational design of an AIDS vaccine. Cell 124, 677-81.
33. Huang, C. C., Tang, M., Zhang, M. Y., Majeed, S., Montabana, E., Stanfield, R. L., Dimitrov, D. S., Korber, B., Sodroski, J., Wilson, I. A., Wyatt, R., and Kwong, P. D. (2005). Structure of a V3-containing HIV-1 gp120 core. Science. 310, 1025-8. PDB: 2b4c.
32. Zhou, T., Hamer, D. H., Hendrickson, W. A., Sattentau, Q. J., and Kwong, P. D. (2005). Interfacial metal and antibody recognition. Proc Natl Acad Sci USA. 102, 14575-80. PDB: 2adj, 2adi, 2adg.
31. Pancera, M., Lebowitz, J., Schon, A., Zhu, P., Freire, E., Kwong, P. D., Roux, K. H., Sodroski, J., and 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. J Virol. 79, 9954-69.
30. Huang, C., Stricher, F., Martin, L., Decker, J. M., Majeed, S., Barthe, P., Hendrickson, W. A., Robinson, J., Roumestand, C., Sodroski, J., Wyatt, R., Shaw, G. M., Vita, C., and Kwong P. D. (2005). Scorpion-toxin mimics of CD4 in complex with human immunodeficiency virus gp120: Crystal structures, molecular mimicry, and neutralization breadth. Structure. 5, 755-68. PDB: 1yyl, 1yym.
29. Decker, J. M., Bibollet-Ruche, F., Wei, X., Wang, S., Levy, D. N., Wang, W., Delaporte, E., Peeters, M., Derdeyn, C. A., Allen, S., Hunter, E., Saag, M. S., Hoxie, J. A., Hahn, B. H., Kwong, P. D., Robinson, J. E., and Shaw, G. M. (2005). Antigenic conservation and immunogenicity of the HIV co-receptor binding site. J Exp Med. 9, 1407-19.
28. Kwong, P. D. (2005). Refolding the envelope. Nature. 433, 815-816.
27. Ofek, G., Tang, M., Sambor, A., Katinger, H., Mascola, J. R., Wyatt, R., and Kwong, P. D. (2004). Structure and mechanistic analysis of the anti-HIV-1 antibody 2F5 in complex with Its gp41 epitope. J Virol. 78, 10724-10737. PDB: 1tjg, 1tjh, 1tji.
26. Huang, C. C., Venturi, M., Majeed, S., Moore, M. J., Phogat, S., Zhang, M. Y., Dimitrov, D. S., Hendrickson, W. A., Robinson, J., Sodroski, J., Wyatt, R., Choe, H., Farzan, M., and Kwong, P. D. (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 USA. 101, 2706-11. PDB: 1rz7, 1rz8, 1rzi, 1rzg, 1rzf, 1rzk, 1rzj.
25. Kwong, P. D. (2004). The 447-52D antibody: Hitting HIV-1 where its armor is thickest. Structure. 12, 173-4.
24. Burton, D. R., Desrosiers, R. C., Doms, R. W., Koff, W. C., Kwong, P. D., Moore, J. P., Nabel, G. J., Sodroski, J., Wilson, I. A., and Wyatt, R. T. (2004). HIV vaccine design and the neutralizing antibody problem. Nat Immunol. 3, 233-6.
23. Xiang, S.-H., Wang, L., Abreu, M., Huang, C., Kwong, P. D., Rosenberg, E., Robinson, J. E., 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.
22. Kock, M., Pancera, M., Kwong, P. D., Kolchinsky, P., Grundner, C., Wang, L., Hendrickson, W. A., 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.
21. Labrijn, A. F., Poignard, P., Raja, A., Zwick, M. B., Delgado, K., Franti, M., Binley, J., Vivona, V., Grundner, C., Huang, C. C., Venturi, M., Petropoulos, C. J., Wrin, T., Dimitrov, D. S., Robinson, J., Kwong, P. D., Wyatt, R. T., Sodroski, J., and Burton, D. R. (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.
20. Majeed, S., Ofek, G., Belachew, A., Huang, C., Zhou, T., and Kwong, P. D. (2003). Enhancing protein crystallization through precipitant synergy. Structure. 11, 1061-1070. PDB: 1ps5.
19. Choe, H., Li, W., Wright, P. L., Vasilieva, N., Venturi, M., Huang, C., Grundner, C., Zwick, M. B., Wang, L., Rosenberg, E. S., Kwong, P. D., Burton, D. R., Robinson, J. E., Sodroski, J. G., and Farzan, M. (2003). Tyrosine sulfation of human antibodies contributes to recognition of the CCR5 binding region of HIV-1 gp120. Cell. 114, 161-170.
18. Wei, X., Decker, J. M., Wang, S., Hui, H., Kappes, J. C., Wu, X., Salazar-Gonzalez, J. F., Salazar, M. G., Kilby, J. M., Saag, M. S., Komarova, N. L., Nowak, M. A., Hahn, B. H., Kwong, P. D., and Shaw, G. M. (2003). Antibody neutralization and escape by HIV-1. Nature. 422, 307-312.
17. Raja, A., Venturi, M., Kwong, P., and Sodroski, J. (2003). CD4 binding site antibodies inhibit human immunodeficiency virus gp120 envelope glycoprotein interaction with CCR5. J Virol. 77, 713-718.
16. Kwong, P. D., Doyle, M. L., Casper, D. J., Cicala, C., Leavitt, S. A., Majeed, S., Steenbeke, T. D., Venturi, M., Chaiken, I., Fung, M., Katinger, H., Parren, P. W., Robinson, J., Van Ryk, D., Wang, L., Burton, D. R., Freire, E., Wyatt, R., Sodroski, J., Hendrickson, W. A., and Arthos, J. (2002). HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature. 420, 678-682.
15. Xiang, S. H., Kwong, P. D., Gupta, R., Rizzuto, C. D., Casper, D. J., Wyatt, R., Wang, L., Hendrickson, W. A., Doyle, M. L., and 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.
14. Sanders, R. W., Venturi, M., Schiffner, L., Kalyanaraman, R., Katinger, H., Lloyd, K. O., Kwong, P. D., and Moore, J. P. (2002). The mannose-dependent epitope for neutralizing antibody 2G12 on human immunodeficiency virus type 1 glycoprotein gp120. J Virol. 76, 7293-7305.
13. Yang, X., Lee, J., Mahony, E. M., Kwong, P. D., Wyatt, R., and 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.
12. Kwong, P. D., Wyatt, R., Majeed, S., Robinson, J., Sweet, R. W., Sodroski, J., and Hendrickson, W. A. (2000). Structures of HIV-1 gp120 envelope glycoproteins from laboratory-adapted and primary isolates. Structure .8, 1329-1339. PDB: 1g9m, 1g9n.
11. Myszka, D. G., Sweet, R. W., Hensley, P., Brigham-Burke, M., Kwong, P. D., Hendrickson, W. A., Wyatt, R., Sodroski, J., and Doyle, M. L. (2000). Energetics of the HIV gp120-CD4 binding reaction. Proc Natl Acad Sci USA. 97, 9026-9031.
10. Yang, X., Florin, L., Farzan, M., Kolchinsky, P. Kwong, P. D., Sodroski, J., and Wyatt, R. (2000). Modifications that stabilize human immunodeficiency virus envelope glycoprotein trimers in solution. J Virol. 74, 4746-4754.
9. Kwong, P. D., Wyatt, R., Sattentau, Q. J., Sodroski, J., and 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. PDB: Trimeric gp120 IRZJ (Zip), Trimeric gp120 HA proportionate (Zip).
8. Moulard, M., Lortat-Jacob, H., Mondor, I., Guillaume, R., Wyatt, R., Sodroski, J., Zhao, L., Olson, W., Kwong, P. D., and Sattentau, Q. J. (2000). Selective polyanion interactions with basic surfaces on human immunodeficiency virus type 1 gp120. J Virol. 74, 1948-1960.
7. Kwong, P. D., Wyatt, R., Desjardins, E., Robinson, J., Culp, J. S., Hellmig, B. D., Sweet, R. W., Sodroski, J., and 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.
6. Kwong, P. D., and Liu, Y. (1999). Use of cryoprotectants in combination with immiscible oils for flash-cooling macromolecular crystals. J. Applied Crystallography. 32, 102-105.
5. Zhang, W., Canziani, G., Plugariu, C., Wyatt, R., Sodroski, J., Sweet, R. W., Kwong, P. D., Hendrickson, W. A., and 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.
4. Binley, J. M., Wyatt, R., Desjardins, E., Kwong, P. D., Hendrickson, W. A., Moore, J. P., and 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.
3. Rizzuto, C. D., Wyatt, R., Hernandez-Ramos, N., Sun, Y., Kwong, P. D., Hendrickson, W. A., and Sodroski, J. (1998). A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding. Science. 280, 1949-1953.
2. Wyatt, R., Kwong, P. D., Desjardins, E., Sweet, R. W., Robinson, J., Hendrickson, W. A., and Sodroski, J. (1998). The antigenic structure of the HIV gp120 envelope glycoprotein. Nature. 393, 705-711.
1. Kwong, P. D., Wyatt, R., Robinson, J., Sweet, R. W., Sodroski, J., and 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. PDB: 1gc1.
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