The W100 pocket on HIV-1 gp120 penetrated by b12 is not a target for other CD4bs monoclonal antibodies

Retrovirology

Paul R Clapham²  Susan Zolla-Pazner¹  Davide Corti³  Olivia J O'Connell²  Maria J Dueñas-Decamp² 

[1] Department of Pathology, New York University Langone School of Medicine, New York, NY 10016;Center for AIDS Research, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, MA 01605;Humabs Biomed SA, Bellinzona, CH-6500, Switzerland

关键词: neutralization;    CD4 binding site;    gp120;    envelope;    HIV;   

Others  :  1209354
DOI  :  10.1186/1742-4690-9-9

 received in 2011-07-19, accepted in 2012-01-27,  发布年份 2012

【 摘 要 】

Background

The conserved CD4 binding site (CD4bs) on HIV-1 gp120 is a major target for vaccines. It is a priority to determine sites and structures within the CD4bs that are important for inclusion in vaccines. We studied a gp120 pocket penetrated by W100 of the potent CD4bs monoclonal antibody (mab), b12. We compared HIV-1 envelopes and corresponding mutants that carried blocked W100 pockets to evaluate whether other CD4bs mabs target this site.

Findings

All CD4bs mabs tested blocked soluble CD4 binding to gp120 consistent with their designation as CD4bs directed antibodies. All CD4bs mabs tested neutralized pseudovirions carrying NL4.3 wild type (wt) envelope. However, only b12 failed to neutralize pseudoviruses carrying mutant envelopes with a blocked W100 pocket. In addition, for CD4bs mabs that neutralized pseudovirions carrying primary envelopes, mutation of the W100 pocket had little or no effect on neutralization sensitivity.

Conclusions

Our data indicate that the b12 W100 pocket on gp120 is infrequently targeted by CD4bs mabs. This site is therefore not a priority for preservation in vaccines aiming to elicit antibodies targeting the CD4bs.

【 授权许可】

   
2012 Dueñas-Decamp et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Duenas-Decamp MJ, Peters P, Burton D, Clapham PR: Natural resistance of human immunodeficiency virus type 1 to the CD4bs antibody b12 conferred by a glycan and an arginine residue close to the CD4 binding loop. J Virol 2008, 82:5807-5814.
• [2]Pantophlet R, Ollmann Sapphire E, Poignard P, Parren PW, Wilson IA, Burton DR: Fine mapping of the interaction of neutralizing and nonneutralizing monoclonal antibodies with the CD4 binding site of human immunodeficiency virus type 1 gp120. J Virol 2003, 77:642-658.
• [3]Sanders RW, van Anken E, Nabatov AA, Liscaljet IM, Bontjer I, Eggink D, Melchers M, Busser E, Dankers MM, Groot F, Braakman I, Berkhout B, Paxton WA: The carbohydrate at asparagine 386 on HIV-1 gp120 is not essential for protein folding and function but is involved in immune evasion. Retrovirology 2008, 5:10. BioMed Central Full Text
• [4]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, 445:732-737.
• [5]Corti D, Langedijk JP, Hinz A, Seaman MS, Vanzetta F, Fernandez-Rodriguez BM, Silacci C, Pinna D, Jarrossay D, Balla-Jhagjhoorsingh S, Willems B, Zekveld MJ, Dreja H, O'Sullivan E, Pade C, Orkin C, Jeffs SA, Montefiori DC, Davis D, Weissenhorn W, McKnight A, Heeney JL, Sallusto F, Sattentau QJ, Weiss RA, Lanzavecchia A: Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals. PLoS One 2010, 5:e8805.
• [6]Zhou T, Georgiev I, Wu X, Yang ZY, Dai K, Finzi A, Do Kwon Y, Scheid J, 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, 330:1775-1787.
• [7]Li Y, O'Dell S, Walker LM, Wu X, Guenaga J, Feng Y, Schmidt SD, McKee K, Louder MK, Ledgerwood JE, Graham BS, Haynes BF, Burton DR, Wyatt RT, Mascola JR: Mechanism of Neutralization by the Broadly Neutralizing HIV-1 Monoclonal Antibody VRC01. J Virol 2011, 85:8954-8967.
• [8]Peters PJ, Duenas-Decamp MJ, Sullivan WM, Brown R, Ankghuambom C, Luzuriaga K, Robinson J, Burton DR, Bell J, Simmonds P, Ball J, Clapham P: Variation in HIV-1 R5 macrophage-tropism correlates with sensitivity to reagents that block envelope: CD4 interactions but not with sensitivity to other entry inhibitors. Retrovirology 2008, 5:5.
• [9]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, 393:648-659.
• [10]Theodore TS, Englund G, Buckler-White A, Buckler CE, Martin MA, Peden KW: Construction and characterization of a stable full-length macrophage-tropic HIV type 1 molecular clone that directs the production of high titers of progeny virions. AIDS Res Hum Retroviruses 1996, 12:191-194.
• [11]Koyanagi Y, Miles S, Mitsuyasu RT, Merrill JE, Vinters HV, Chen IS: Dual infection of the central nervous system by AIDS viruses with distinct cellular tropisms. Science 1987, 236:819-822.
• [12]Peters PJ, Bhattacharya J, Hibbitts S, Dittmar MT, Simmons G, Bell J, Simmonds P, Clapham PR: Biological analysis of human immunodeficiency virus type 1 R5 envelopes amplified from brain and lymph node tissues of AIDS patients with neuropathology reveals two distinct tropism phenotypes and identifies envelopes in the brain that confer an enhanced tropism and fusigenicity for macrophages. J Virol 2004, 78:6915-6926.
• [13]Scheid JF, Mouquet H, Ueberheide B, Diskin R, Klein F, Olivera TY, Pietzsch J, Fenyo D, Abadir A, Velinzon K, Hurley A, Myung S, Boulad F, Poignard P, Burton D, Pereyra F, Ho DD, Walker BD, Seaman MS, Bjorkman PJ, Chait BT, Nussenzweig MC: Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding. Science 2011, 333:1633-1637.
• [14]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 N, Connors M, 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, 333:1593-1602.
• [15]Clapham PR, Lu S: Vaccinology: precisely tuned antibodies nab HIV. Nature 2011, 477:416-417.
• [16]Diskin R, Scheid JF, Marcovecchio PM, West AP Jr, Klein F, Gao H, Gnanapragasam PN, Abadir A, Seaman MS, Nussenzweig MC, Bjorkman PJ: Increasing the Potency and Breadth of an HIV Antibody by Using Structure-Based Rational Design. Science 2011, 334:1289-1293.
• [17]Jacobson JM, Lowy I, Fletcher CV, O'Neill TJ, Tran DN, Ketas TJ, Trkola A, Klotman ME, Maddon PJ, Olson WC, Israel RJ: Single-dose safety, pharmacology, and antiviral activity of the human immunodeficiency virus (HIV) type 1 entry inhibitor PRO 542 in HIV-infected adults. J Infect Dis 2000, 182:326-329.
• [18]Chen L, Kwon YD, Zhou T, Wu X, O'Dell S, Cavacini L, Hessell AJ, Pancera M, Tang M, Xu L, Yang ZY, Zhang MY, Arthos J, Burton DR, Dimitrov DS, Nabel GJ, Posner MR, Sodroski J, Wyatt R, Mascola JR, Kwong PD: Structural basis of immune evasion at the site of CD4 attachment on HIV-1 gp120. Science 2009, 326:1123-1127.
• [19]Wilkinson RA, Piscitelli C, Teintze M, Cavacini LA, Posner MR, Lawrence CM: Structure of the Fab fragment of F105, a broadly reactive anti-human immunodeficiency virus (HIV) antibody that recognizes the CD4 binding site of HIV type 1 gp120. J Virol 2005, 79:13060-13069.
• [20]Laal S, Burda S, Gorny MK, Karwowska S, Buchbinder A, Zolla-Pazner S: Synergistic neutralization of human immunodeficiency virus type 1 by combinations of human monoclonal antibodies. J Virol 1994, 68:4001-4008.
• [21]Ho DD, McKeating JA, Li XL, Moudgil T, Daar ES, Sun NC, Robinson JE: Conformational epitope on gp120 important in CD4 binding and human immunodeficiency virus type 1 neutralization identified by a human monoclonal antibody. J Virol 1991, 65:489-493.
• [22]Zhang MY, Dimitrov DS: Novel approaches for identification of broadly cross-reactive HIV-1 neutralizing human monoclonal antibodies and improvement of their potency. Curr Pharm Des 2007, 13:203-212.
• [23]Schutten M, McKnight A, Huisman RC, Thali M, McKeating JA, Sodroski J, Goudsmit J, Osterhaus AD: Further characterization of an antigenic site of HIV-1 gp120 recognized by virus neutralizing human monoclonal antibodies. AIDS 1993, 7:919-923.
• [24]Jeffs SA, Gorny MK, Williams C, Revesz K, Volsky B, Burda S, Wang XH, Bandres J, Zolla-Pazner S, Holmes H: Characterization of human monoclonal antibodies selected with a hypervariable loop-deleted recombinant HIV-1(IIIB) gp120. Immunol Lett 2001, 79:209-213.
• [25]McKeating JA, Thali M, Furman C, Karwowska S, Gorny MK, Cordell J, Zolla Pazner S, Sodroski J, Weiss RA: Amino acid residues of the human immunodeficiency virus type I gp120 critical for the binding of rat and human neutralizing antibodies that block the gp120-sCD4 interaction. Virology 1992, 190:134-142.