Characterization of a Prefusion-Specific Antibody That Recognizes a Quaternary, Cleavage-Dependent Epitope on the RSV Fusion Glycoprotein

English version České info

Respiratory syncytial virus (RSV) causes significant morbidity and mortality in children, yet an efficacious vaccine remains unavailable. Antibodies that preferentially recognize the prefusion conformation of the fusion (F) glycoprotein, particularly those that bind antigenic site Ø at the membrane-distal apex, potently neutralize infection and have aided vaccine design. Here we characterize AM14, a potent human antibody, which we show recognizes a novel epitope midway between the membrane-proximal region and the apex of the prefusion F trimer. The epitope is evenly distributed across two protomers, causing AM14 to be uniquely trimer-specific and, surprisingly, cleavage-dependent. These results indicate that the prefusion trimer is antigenically distinct from the monomer. Our findings also demonstrate that epitopes other than site Ø can be the target of extremely potent neutralizing antibodies and thus provide a new target for structure-based vaccine design. Recognition of this novel epitope could make AM14 an ideal candidate for strategies that combine passive prophylaxis with vaccination, since binding of AM14 would not block elicitation of antibodies against site Ø. Due to its unique specificity, AM14 will also be valuable for probing the conformation of RSV F-based vaccine antigens designed to be in the furin-cleaved trimeric prefusion conformation.

Vyšlo v časopise: Characterization of a Prefusion-Specific Antibody That Recognizes a Quaternary, Cleavage-Dependent Epitope on the RSV Fusion Glycoprotein. PLoS Pathog 11(7): e32767. doi:10.1371/journal.ppat.1005035
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005035

Souhrn

Zdroje

1. Glezen WP, Taber LH, Frank AL, Kasel JA. Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child. 1986;140(6): 543–546. 3706232

2. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859): 2095–2128. doi: 10.1016/S0140-6736(12)61728-0 23245604

3. Byington CL, Wilkes J, Korgenski K, Sheng X. Respiratory syncytial virus-associated mortality in hospitalized infants and young children. Pediatrics. 2015;135(1): e24–31. doi: 10.1542/peds.2014-2151 25489019

4. Leader S, Kohlhase K. Recent trends in severe respiratory syncytial virus (RSV) among US infants, 1997 to 2000. J Pediatr. 2003;143(5 Suppl): S127–132. 14615711

5. Homaira N, Rawlinson W, Snelling TL, Jaffe A. Effectiveness of Palivizumab in Preventing RSV Hospitalization in High Risk Children: A Real-World Perspective. Int J Pediatr. 2014;2014 : 571609. doi: 10.1155/2014/571609 25548575

6. The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics. 1998;102(3 Pt 1): 531–537. 9738173

7. Kamal-Bahl S, Doshi J, Campbell J. Economic analyses of respiratory syncytial virus immunoprophylaxis in high-risk infants: a systematic review. Arch Pediatr Adolesc Med. 2002;156(10): 1034–1041. 12361451

8. Karron RA, Buonagurio DA, Georgiu AF, Whitehead SS, Adamus JE, Clements-Mann ML, et al. Respiratory syncytial virus (RSV) SH and G proteins are not essential for viral replication in vitro: clinical evaluation and molecular characterization of a cold-passaged, attenuated RSV subgroup B mutant. Proc Natl Acad Sci U S A. 1997;94(25): 13961–13966. 9391135

9. Beeler JA, van Wyke Coelingh K. Neutralization epitopes of the F glycoprotein of respiratory syncytial virus: effect of mutation upon fusion function. J Virol. 1989;63(7): 2941–2950. 2470922

10. Johnson S, Oliver C, Prince GA, Hemming VG, Pfarr DS, Wang SC, et al. Development of a humanized monoclonal antibody (MEDI-493) with potent in vitro and in vivo activity against respiratory syncytial virus. J Infect Dis. 1997;176(5): 1215–1224. 9359721

11. McLellan JS, Chen M, Kim A, Yang Y, Graham BS, Kwong PD. Structural basis of respiratory syncytial virus neutralization by motavizumab. Nat Struct Mol Biol. 2010;17(2): 248–250. doi: 10.1038/nsmb.1723 20098425

12. Sastre P, Melero JA, Garcia-Barreno B, Palomo C. Comparison of affinity chromatography and adsorption to vaccinia virus recombinant infected cells for depletion of antibodies directed against respiratory syncytial virus glycoproteins present in a human immunoglobulin preparation. J Med Virol. 2005;76(2): 248–255. 15834867

13. Gonzalez-Reyes L, Ruiz-Arguello MB, Garcia-Barreno B, Calder L, Lopez JA, Albar JP, et al. Cleavage of the human respiratory syncytial virus fusion protein at two distinct sites is required for activation of membrane fusion. Proc Natl Acad Sci U S A. 2001;98(17): 9859–9864. 11493675

14. Bolt G, Pedersen LO, Birkeslund HH. Cleavage of the respiratory syncytial virus fusion protein is required for its surface expression: role of furin. Virus Res. 2000;68(1): 25–33. 10930660

15. Begona Ruiz-Arguello M, Gonzalez-Reyes L, Calder LJ, Palomo C, Martin D, Saiz MJ, et al. Effect of proteolytic processing at two distinct sites on shape and aggregation of an anchorless fusion protein of human respiratory syncytial virus and fate of the intervening segment. Virology. 2002;298(2): 317–326. 12127793

16. Scheid A, Choppin PW. Two disulfide-linked polypeptide chains constitute the active F protein of paramyxoviruses. Virology. 1977;80(1): 54–66. 195398

17. Swanson KA, Settembre EC, Shaw CA, Dey AK, Rappuoli R, Mandl CW, et al. Structural basis for immunization with postfusion respiratory syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers. Proc Natl Acad Sci U S A. 2011;108(23): 9619–9624. doi: 10.1073/pnas.1106536108 21586636

18. McLellan JS, Yang Y, Graham BS, Kwong PD. Structure of respiratory syncytial virus fusion glycoprotein in the postfusion conformation reveals preservation of neutralizing epitopes. J Virol. 2011;85(15): 7788–7796. doi: 10.1128/JVI.00555-11 21613394

19. McLellan JS, Chen M, Leung S, Graepel KW, Du X, Yang Y, et al. Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody. Science. 2013;340(6136): 1113–1117. doi: 10.1126/science.1234914 23618766

20. McLellan JS, Ray WC, Peeples ME. Structure and function of respiratory syncytial virus surface glycoproteins. Curr Top Microbiol Immunol. 2013;372 : 83–104. doi: 10.1007/978-3-642-38919-1_4 24362685

21. Liljeroos L, Krzyzaniak MA, Helenius A, Butcher SJ. Architecture of respiratory syncytial virus revealed by electron cryotomography. Proc Natl Acad Sci U S A. 2013;110(27): 11133–11138. doi: 10.1073/pnas.1309070110 23776214

22. McLellan JS, Chen M, Chang JS, Yang Y, Kim A, Graham BS, et al. Structure of a major antigenic site on the respiratory syncytial virus fusion glycoprotein in complex with neutralizing antibody 101F. J Virol. 2010;84(23): 12236–12244. doi: 10.1128/JVI.01579-10 20881049

23. Kwakkenbos MJ, Diehl SA, Yasuda E, Bakker AQ, van Geelen CM, Lukens MV, et al. Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming. Nat Med. 2010;16(1): 123–128. doi: 10.1038/nm.2071 20023635

24. Magro M, Mas V, Chappell K, Vazquez M, Cano O, Luque D, et al. Neutralizing antibodies against the preactive form of respiratory syncytial virus fusion protein offer unique possibilities for clinical intervention. Proc Natl Acad Sci U S A. 2012;109(8): 3089–3094. doi: 10.1073/pnas.1115941109 22323598

25. Corti D, Bianchi S, Vanzetta F, Minola A, Perez L, Agatic G, et al. Cross-neutralization of four paramyxoviruses by a human monoclonal antibody. Nature. 2013;501(7467): 439–443. doi: 10.1038/nature12442 23955151

26. McLellan JS, Chen M, Joyce MG, Sastry M, Stewart-Jones GB, Yang Y, et al. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science. 2013;342(6158): 592–598. doi: 10.1126/science.1243283 24179220

27. Swanson KA, Balabanis K, Xie Y, Aggarwal Y, Palomo C, Mas V, et al. A monomeric uncleaved respiratory syncytial virus F antigen retains prefusion-specific neutralizing epitopes. J Virol. 2014;88(20): 11802–11810. doi: 10.1128/JVI.01225-14 25078705

28. Johnson S, Griego SD, Pfarr DS, Doyle ML, Woods R, Carlin D, et al. A direct comparison of the activities of two humanized respiratory syncytial virus monoclonal antibodies: MEDI-493 and RSHZl9. J Infect Dis. 1999;180(1): 35–40. 10353858

29. Blattner C, Lee JH, Sliepen K, Derking R, Falkowska E, de la Pena AT, et al. Structural delineation of a quaternary, cleavage-dependent epitope at the gp41-gp120 interface on intact HIV-1 Env trimers. Immunity. 2014;40(5): 669–680. doi: 10.1016/j.immuni.2014.04.008 24768348

30. Huang J, Kang BH, Pancera M, Lee JH, Tong T, Feng Y, et al. Broad and potent HIV-1 neutralization by a human antibody that binds the gp41-gp120 interface. Nature. 2014;515(7525): 138–142. doi: 10.1038/nature13601 25186731

31. Magadan JG, Khurana S, Das SR, Frank GM, Stevens J, Golding H, et al. Influenza A virus hemagglutinin trimerization completes monomer folding and antigenicity. J Virol. 2013;87(17): 9742–9753. doi: 10.1128/JVI.00471-13 23824811

32. Falkowska E, Le KM, Ramos A, Doores KJ, Lee JH, Blattner C, et al. Broadly neutralizing HIV antibodies define a glycan-dependent epitope on the prefusion conformation of gp41 on cleaved envelope trimers. Immunity. 2014;40(5): 657–668. doi: 10.1016/j.immuni.2014.04.009 24768347

33. Gigant B, Barbey-Martin C, Bizebard T, Fleury D, Daniels R, Skehel JJ, et al. A neutralizing antibody Fab-influenza haemagglutinin complex with an unprecedented 2 : 1 stoichiometry: characterization and crystallization. Acta Crystallogr D Biol Crystallogr. 2000;56(Pt 8): 1067–1069. 10944356

34. Barbey-Martin C, Gigant B, Bizebard T, Calder LJ, Wharton SA, Skehel JJ, et al. An antibody that prevents the hemagglutinin low pH fusogenic transition. Virology. 2002;294(1): 70–74. 11886266

35. Rouvinski A, Guardado-Calvo P, Barba-Spaeth G, Duquerroy S, Vaney MC, Kikuti CM, et al. Recognition determinants of broadly neutralizing human antibodies against dengue viruses. Nature. 2015;520(7545): 109–113. doi: 10.1038/nature14130 25581790

36. Kaufmann B, Vogt MR, Goudsmit J, Holdaway HA, Aksyuk AA, Chipman PR, et al. Neutralization of West Nile virus by cross-linking of its surface proteins with Fab fragments of the human monoclonal antibody CR4354. Proc Natl Acad Sci U S A. 2010;107(44): 18950–18955. doi: 10.1073/pnas.1011036107 20956322

37. Yin HS, Wen X, Paterson RG, Lamb RA, Jardetzky TS. Structure of the parainfluenza virus 5 F protein in its metastable, prefusion conformation. Nature. 2006;439(7072): 38–44. 16397490

38. Welch BD, Liu Y, Kors CA, Leser GP, Jardetzky TS, Lamb RA. Structure of the cleavage-activated prefusion form of the parainfluenza virus 5 fusion protein. Proc Natl Acad Sci U S A. 2012;109(41): 16672–16677. doi: 10.1073/pnas.1213802109 23012473

39. Copeland CS, Doms RW, Bolzau EM, Webster RG, Helenius A. Assembly of influenza hemagglutinin trimers and its role in intracellular transport. J Cell Biol. 1986;103(4): 1179–1191. 2429970

40. Yewdell JW, Yellen A, Bachi T. Monoclonal antibodies localize events in the folding, assembly, and intracellular transport of the influenza virus hemagglutinin glycoprotein. Cell. 1988;52(6): 843–852. 2450677

41. Mastronarde DN. Automated electron microscope tomography using robust prediction of specimen movements. J Struct Biol. 2005;152(1): 36–51. 16182563

42. Tang G, Peng L, Baldwin PR, Mann DS, Jiang W, Rees I, et al. EMAN2: an extensible image processing suite for electron microscopy. J Struct Biol. 2007;157(1): 38–46. 16859925

43. Warkentin M, Berejnov V, Husseini NS, Thorne RE. Hyperquenching for protein cryocrystallography. J Appl Crystallogr. 2006;39(6): 805–811. 20461232

44. Battye TG, Kontogiannis L, Johnson O, Powell HR, Leslie AG. iMOSFLM: a new graphical interface for diffraction-image processing with MOSFLM. Acta Crystallogr D Biol Crystallogr. 2011;67(Pt 4): 271–281. doi: 10.1107/S0907444910048675 21460445

45. Evans PR, Murshudov GN. How good are my data and what is the resolution? Acta Crystallogr D Biol Crystallogr. 2013;69(Pt 7): 1204–1214. doi: 10.1107/S0907444913000061 23793146

46. McCoy AJ, Grosse-Kunstleve RW, Adams PD, Winn MD, Storoni LC, Read RJ. Phaser crystallographic software. J Appl Crystallogr. 2007;40(Pt 4): 658–674. 19461840

47. Koth CM, Murray JM, Mukund S, Madjidi A, Minn A, Clarke HJ, et al. Molecular basis for negative regulation of the glucagon receptor. Proc Natl Acad Sci U S A. 2012;109(36): 14393–14398. doi: 10.1073/pnas.1206734109 22908259

48. Emsley P, Cowtan K. Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr. 2004;60(Pt 12 Pt 1): 2126–2132. 15572765

49. Adams PD, Grosse-Kunstleve RW, Hung LW, Ioerger TR, McCoy AJ, Moriarty NW, et al. PHENIX: building new software for automated crystallographic structure determination. Acta Crystallogr D Biol Crystallogr. 2002;58(Pt 11): 1948–1954. 12393927

50. Wu H, Pfarr DS, Tang Y, An LL, Patel NK, Watkins JD, et al. Ultra-potent antibodies against respiratory syncytial virus: effects of binding kinetics and binding valence on viral neutralization. J Mol Biol. 2005;350(1): 126–144. 15907931

51. Budge PJ, Li Y, Beeler JA, Graham BS. RhoA-derived peptide dimers share mechanistic properties with other polyanionic inhibitors of respiratory syncytial virus (RSV), including disruption of viral attachment and dependence on RSV G. J Virol. 2004;78(10): 5015–5022. 15113882

52. Chen M, Chang JS, Nason M, Rangel D, Gall JG, Graham BS, et al. A flow cytometry-based assay to assess RSV-specific neutralizing antibody is reproducible, efficient and accurate. J Immunol Methods. 2010;362(1–2): 180–184. doi: 10.1016/j.jim.2010.08.005 20727896