Human monoclonal antibodies against chikungunya virus target multiple distinct epitopes in the E1 and E2 glycoproteins

English version

Autoři: Jose A. Quiroz ^aff001; Ryan J. Malonis ^aff001; Larissa B. Thackray ^aff002; Courtney A. Cohen ^aff003; Jesper Pallesen ^aff004; Rohit K. Jangra ^aff005; Rebecca S. Brown ^aff006; Daniel Hofmann ^aff001; Frederick W. Holtsberg ^aff007; Sergey Shulenin ^aff007; Elisabeth K. Nyakatura ^aff001; Lorellin A. Durnell ^aff002; Vinayak Rayannavar ^aff001; Johanna P. Daily ^aff008; Andrew B. Ward ^aff004; M. Javad Aman ^aff007; John M. Dye ^aff003; Kartik Chandran ^aff005; Michael S. Diamond ^aff002; Margaret Kielian ^aff006; Jonathan R. Lai ^aff001
Působiště autorů: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, United States of America ^aff001; Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, United States of America ^aff002; Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America ^aff003; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America ^aff004; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America ^aff005; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America ^aff006; Integrated Biotherapeutics Inc., Rockville, Maryland, United States of America ^aff007; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America ^aff008; Department of Molecular Microbiology, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, United States of America ^aff009; Department of Pathology & Immunology, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, United States of America ^aff010
Vyšlo v časopise: Human monoclonal antibodies against chikungunya virus target multiple distinct epitopes in the E1 and E2 glycoproteins. PLoS Pathog 15(11): e32767. doi:10.1371/journal.ppat.1008061
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008061

Souhrn

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes persistent arthritis in a subset of human patients. We report the isolation and functional characterization of monoclonal antibodies (mAbs) from two patients infected with CHIKV in the Dominican Republic. Single B cell sorting yielded a panel of 46 human mAbs of diverse germline lineages that targeted epitopes within the E1 or E2 glycoproteins. MAbs that recognized either E1 or E2 proteins exhibited neutralizing activity. Viral escape mutations localized the binding epitopes for two E1 mAbs to sites within domain I or the linker between domains I and III; and for two E2 mAbs between the β-connector region and the B-domain. Two of the E2-specific mAbs conferred protection in vivo in a stringent lethal challenge mouse model of CHIKV infection, whereas the E1 mAbs did not. These results provide insight into human antibody response to CHIKV and identify candidate mAbs for therapeutic intervention.

Klíčová slova:

Antibodies – Enzyme-linked immunoassays – Chikungunya infection – Immunoprecipitation – Microbial mutation – Viral structure – Chikungunya virus – Viral entry

Zdroje

1. Jose J, Snyder JE, Kuhn RJ. A structural and functional perspective of alphavirus replication and assembly. Future Microbiol. 2009;4(7):837–56. Epub 2009/09/03. doi: 10.2217/fmb.09.59 19722838; PubMed Central PMCID: PMC2762864.

2. Sourisseau M, Schilte C, Casartelli N, Trouillet C, Guivel-Benhassine F, Rudnicka D, et al. Characterization of reemerging chikungunya virus. PLoS Pathog. 2007;3(6):e89. Epub 2007/07/03. doi: 10.1371/journal.ppat.0030089 17604450; PubMed Central PMCID: PMC1904475.

3. Schuffenecker I, Iteman I, Michault A, Murri S, Frangeul L, Vaney MC, et al. Genome microevolution of chikungunya viruses causing the Indian Ocean outbreak. PLoS Med. 2006;3(7):e263. Epub 2006/05/17. doi: 10.1371/journal.pmed.0030263 16700631; PubMed Central PMCID: PMC1463904.

4. Morrison TE. Reemergence of chikungunya virus. Journal of virology. 2014;88(20):11644–7. Epub 2014/08/01. doi: 10.1128/JVI.01432-14 25078691; PubMed Central PMCID: PMC4178719.

5. Halstead SB. Reappearance of chikungunya, formerly called dengue, in the Americas. Emerging infectious diseases. 2015;21(4):557–61. Epub 2015/03/31. doi: 10.3201/eid2104.141723 25816211; PubMed Central PMCID: PMC4378492.

6. Tsetsarkin KA, Vanlandingham DL, McGee CE, Higgs S. A single mutation in chikungunya virus affects vector specificity and epidemic potential. PLoS Pathog. 2007;3(12):e201. Epub 2007/12/12. doi: 10.1371/journal.ppat.0030201 18069894; PubMed Central PMCID: PMC2134949.

7. Kraemer MU, Sinka ME, Duda KA, Mylne AQ, Shearer FM, Barker CM, et al. The global distribution of the arbovirus vectors Aedes aegypti and Ae. albopictus. Elife. 2015;4:e08347. Epub 2015/07/01. doi: 10.7554/eLife.08347 26126267; PubMed Central PMCID: PMC4493616.

8. Sanchez-San Martin C, Liu CY, Kielian M. Dealing with low pH: entry and exit of alphaviruses and flaviviruses. Trends Microbiol. 2009;17(11):514–21. Epub 2009/10/03. doi: 10.1016/j.tim.2009.08.002 19796949; PubMed Central PMCID: PMC2783195.

9. Voss JE, Vaney MC, Duquerroy S, Vonrhein C, Girard-Blanc C, Crublet E, et al. Glycoprotein organization of Chikungunya virus particles revealed by X-ray crystallography. Nature. 2010;468(7324):709–12. Epub 2010/12/03. doi: 10.1038/nature09555 21124458.

10. Long F, Fong RH, Austin SK, Chen Z, Klose T, Fokine A, et al. Cryo-EM structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity. Proceedings of the National Academy of Sciences of the United States of America. 2015;112(45):13898–903. Epub 2015/10/28. doi: 10.1073/pnas.1515558112 26504196; PubMed Central PMCID: PMC4653152.

11. Sun S, Xiang Y, Akahata W, Holdaway H, Pal P, Zhang X, et al. Structural analyses at pseudo atomic resolution of Chikungunya virus and antibodies show mechanisms of neutralization. Elife. 2013;2:e00435. Epub 2013/04/12. doi: 10.7554/eLife.00435 23577234; PubMed Central PMCID: PMC3614025.

12. Uchime O, Fields W, Kielian M. The role of E3 in pH protection during alphavirus assembly and exit. Journal of virology. 2013;87(18):10255–62. Epub 2013/07/19. doi: 10.1128/JVI.01507-13 23864626; PubMed Central PMCID: PMC3754015.

13. Sjoberg M, Lindqvist B, Garoff H. Activation of the alphavirus spike protein is suppressed by bound E3. Journal of virology. 2011;85(11):5644–50. Epub 2011/03/25. doi: 10.1128/JVI.00130-11 21430054; PubMed Central PMCID: PMC3094962.

14. Wahlberg JM, Boere WA, Garoff H. The heterodimeric association between the membrane proteins of Semliki Forest virus changes its sensitivity to low pH during virus maturation. Journal of virology. 1989;63(12):4991–7. Epub 1989/12/01. 2479769; PubMed Central PMCID: PMC251158.

15. Zhang R, Kim AS, Fox JM, Nair S, Basore K, Klimstra WB, et al. Mxra8 is a receptor for multiple arthritogenic alphaviruses. Nature. 2018;557(7706):570–4. Epub 2018/05/18. doi: 10.1038/s41586-018-0121-3 29769725; PubMed Central PMCID: PMC5970976.

16. Basore K, Kim AS, Nelson CA, Zhang R, Smith BK, Uranga C, et al. Cryo-EM Structure of Chikungunya Virus in Complex with the Mxra8 Receptor. Cell. 2019;177(7):1725–37.e16. Epub 2019/05/14. doi: 10.1016/j.cell.2019.04.006 31080061.

17. Song H, Zhao Z, Chai Y, Jin X, Li C, Yuan F, et al. Molecular Basis of Arthritogenic Alphavirus Receptor MXRA8 Binding to Chikungunya Virus Envelope Protein. Cell. 2019;177(7):1714–24.e12. Epub 2019/05/14. doi: 10.1016/j.cell.2019.04.008 31080063.

18. Ramsauer K, Schwameis M, Firbas C, Mullner M, Putnak RJ, Thomas SJ, et al. Immunogenicity, safety, and tolerability of a recombinant measles-virus-based chikungunya vaccine: a randomised, double-blind, placebo-controlled, active-comparator, first-in-man trial. The Lancet Infectious diseases. 2015;15(5):519–27. Epub 2015/03/06. doi: 10.1016/S1473-3099(15)70043-5 25739878.

19. Chang LJ, Dowd KA, Mendoza FH, Saunders JG, Sitar S, Plummer SH, et al. Safety and tolerability of chikungunya virus-like particle vaccine in healthy adults: a phase 1 dose-escalation trial. Lancet (London, England). 2014;384(9959):2046–52. Epub 2014/08/19. doi: 10.1016/S0140-6736(14)61185-5 25132507.

20. Goo L, Dowd KA, Lin TY, Mascola JR, Graham BS, Ledgerwood JE, et al. A Virus-Like Particle Vaccine Elicits Broad Neutralizing Antibody Responses in Humans to All Chikungunya Virus Genotypes. The Journal of infectious diseases. 2016;214(10):1487–91. Epub 2016/10/30. doi: 10.1093/infdis/jiw431 27655868; PubMed Central PMCID: PMC5091377.

21. Erasmus JH, Rossi SL, Weaver SC. Development of Vaccines for Chikungunya Fever. The Journal of infectious diseases. 2016;214(suppl 5):S488–s96. Epub 2016/12/07. doi: 10.1093/infdis/jiw271 27920179; PubMed Central PMCID: PMC5137239.

22. Levitt NH, Ramsburg HH, Hasty SE, Repik PM, Cole FE Jr., Lupton HW. Development of an attenuated strain of chikungunya virus for use in vaccine production. Vaccine. 1986;4(3):157–62. Epub 1986/09/01. doi: 10.1016/0264-410x(86)90003-4 3020820.

23. Zhu Q, McLellan JS, Kallewaard NL, Ulbrandt ND, Palaszynski S, Zhang J, et al. A highly potent extended half-life antibody as a potential RSV vaccine surrogate for all infants. Science translational medicine. 2017;9(388). Epub 2017/05/05. doi: 10.1126/scitranslmed.aaj1928 28469033.

24. Broeckel R, Fox JM, Haese N, Kreklywich CN, Sukulpovi-Petty S, Legasse A, et al. Therapeutic administration of a recombinant human monoclonal antibody reduces the severity of chikungunya virus disease in rhesus macaques. PLoS neglected tropical diseases. 2017;11(6):e0005637. Epub 2017/06/20. doi: 10.1371/journal.pntd.0005637 28628616; PubMed Central PMCID: PMC5491320.

25. Fox JM, Long F, Edeling MA, Lin H, van Duijl-Richter MK, Fong RH, et al. Broadly Neutralizing Alphavirus Antibodies Bind an Epitope on E2 and Inhibit Entry and Egress. Cell. 2015;163(5):1095–107. Epub 2015/11/11. doi: 10.1016/j.cell.2015.10.050 26553503; PubMed Central PMCID: PMC4659373.

26. Fric J, Bertin-Maghit S, Wang CI, Nardin A, Warter L. Use of human monoclonal antibodies to treat Chikungunya virus infection. The Journal of infectious diseases. 2013;207(2):319–22. Epub 2012/11/06. doi: 10.1093/infdis/jis674 23125446.

27. Jin J, Galaz-Montoya JG, Sherman MB, Sun SY, Goldsmith CS, O'Toole ET, et al. Neutralizing Antibodies Inhibit Chikungunya Virus Budding at the Plasma Membrane. Cell host & microbe. 2018;24(3):417–28.e5. Epub 2018/08/28. doi: 10.1016/j.chom.2018.07.018 30146390; PubMed Central PMCID: PMC6137268.

28. Pal P, Dowd KA, Brien JD, Edeling MA, Gorlatov S, Johnson S, et al. Development of a Highly Protective Combination Monoclonal Antibody Therapy against Chikungunya Virus. PLoS Pathog. 2013;9(4):e1003312. doi: 10.1371/journal.ppat.1003312 23637602

29. Pal P, Fox JM, Hawman DW, Huang YJ, Messaoudi I, Kreklywich C, et al. Chikungunya viruses that escape monoclonal antibody therapy are clinically attenuated, stable, and not purified in mosquitoes. Journal of virology. 2014;88(15):8213–26. Epub 2014/05/16. doi: 10.1128/JVI.01032-14 24829346; PubMed Central PMCID: PMC4135940.

30. Selvarajah S, Sexton NR, Kahle KM, Fong RH, Mattia KA, Gardner J, et al. A neutralizing monoclonal antibody targeting the acid-sensitive region in chikungunya virus E2 protects from disease. PLoS neglected tropical diseases. 2013;7(9):e2423. Epub 2013/09/27. doi: 10.1371/journal.pntd.0002423 24069479; PubMed Central PMCID: PMC3772074.

31. Smith SA, Silva LA, Fox JM, Flyak AI, Kose N, Sapparapu G, et al. Isolation and Characterization of Broad and Ultrapotent Human Monoclonal Antibodies with Therapeutic Activity against Chikungunya Virus. Cell host & microbe. 2015;18(1):86–95. Epub 2015/07/15. doi: 10.1016/j.chom.2015.06.009 26159721; PubMed Central PMCID: PMC4501771.

32. Kose N, Fox JM, Sapparapu G, Bombardi R, Tennekoon RN, de Silva AD, et al. A lipid-encapsulated mRNA encoding a potently neutralizing human monoclonal antibody protects against chikungunya infection. Science immunology. 2019;4(35). Epub 2019/05/19. doi: 10.1126/sciimmunol.aaw6647 31101672; PubMed Central PMCID: PMC6629435.

33. Tiller T, Meffre E, Yurasov S, Tsuiji M, Nussenzweig MC, Wardemann H. Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J Immunol Methods. 2008;329(1–2):112–24. Epub 2007/11/13. doi: 10.1016/j.jim.2007.09.017 17996249; PubMed Central PMCID: PMC2243222.

34. Townsend CL, Laffy JM, Wu YB, Silva O'Hare J, Martin V, Kipling D, et al. Significant Differences in Physicochemical Properties of Human Immunoglobulin Kappa and Lambda CDR3 Regions. Frontiers in immunology. 2016;7:388. Epub 2016/10/13. doi: 10.3389/fimmu.2016.00388 27729912; PubMed Central PMCID: PMC5037968.

35. Mazor Y, Barnea I, Keydar I, Benhar I. Antibody internalization studied using a novel IgG binding toxin fusion. J Immunol Methods. 2007;321(1–2):41–59. Epub 2007/03/06. doi: 10.1016/j.jim.2007.01.008 17336321.

36. Chen G, Koellhoffer JF, Zak SE, Frei JC, Liu N, Long H, et al. Synthetic Antibodies with a Human Framework That Protect Mice from Lethal Sudan Ebolavirus Challenge. ACS chemical biology. 2014;9(10):2263–73. doi: 10.1021/cb5006454 25140871

37. Chattopadhyay A, Wang E, Seymour R, Weaver SC, Rose JK. A chimeric vesiculo/alphavirus is an effective alphavirus vaccine. Journal of virology. 2013;87(1):395–402. Epub 2012/10/19. doi: 10.1128/JVI.01860-12 23077320; PubMed Central PMCID: PMC3536361.

38. Whitt MA, Geisbert TW, Mire CE. Single-Vector, Single-Injection Recombinant Vesicular Stomatitis Virus Vaccines Against High-Containment Viruses. Methods in molecular biology (Clifton, NJ). 2016;1403:295–311. Epub 2016/04/15. doi: 10.1007/978-1-4939-3387-7_16 27076138.

39. Agnandji ST, Huttner A, Zinser ME, Njuguna P, Dahlke C, Fernandes JF, et al. Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe. The New England journal of medicine. 2016;374(17):1647–60. Epub 2015/04/02. doi: 10.1056/NEJMoa1502924 25830326; PubMed Central PMCID: PMC5490784.

40. Ge P, Tsao J, Schein S, Green TJ, Luo M, Zhou ZH. Cryo-EM model of the bullet-shaped vesicular stomatitis virus. Science (New York, NY). 2010;327(5966):689–93. Epub 2010/02/06. doi: 10.1126/science.1181766 20133572; PubMed Central PMCID: PMC2892700.

41. Jin J, Liss NM, Chen DH, Liao M, Fox JM, Shimak RM, et al. Neutralizing Monoclonal Antibodies Block Chikungunya Virus Entry and Release by Targeting an Epitope Critical to Viral Pathogenesis. Cell reports. 2015;13(11):2553–64. Epub 2015/12/22. doi: 10.1016/j.celrep.2015.11.043 26686638; PubMed Central PMCID: PMC4720387.

42. Sanchez-San Martin C, Nanda S, Zheng Y, Fields W, Kielian M. Cross-inhibition of chikungunya virus fusion and infection by alphavirus E1 domain III proteins. Journal of virology. 2013;87(13):7680–7. Epub 2013/05/03. doi: 10.1128/JVI.00814-13 23637415; PubMed Central PMCID: PMC3700285.

43. Gibbons DL, Vaney MC, Roussel A, Vigouroux A, Reilly B, Lepault J, et al. Conformational change and protein-protein interactions of the fusion protein of Semliki Forest virus. Nature. 2004;427(6972):320–5. Epub 2004/01/23. doi: 10.1038/nature02239 14737160.

44. Sheehan KC, Lai KS, Dunn GP, Bruce AT, Diamond MS, Heutel JD, et al. Blocking monoclonal antibodies specific for mouse IFN-alpha/beta receptor subunit 1 (IFNAR-1) from mice immunized by in vivo hydrodynamic transfection. Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research. 2006;26(11):804–19. Epub 2006/11/23. doi: 10.1089/jir.2006.26.804 17115899.

45. Saphire EO, Schendel SL, Fusco ML, Gangavarapu K, Gunn BM, Wec AZ, et al. Systematic Analysis of Monoclonal Antibodies against Ebola Virus GP Defines Features that Contribute to Protection. Cell. 2018;174(4):938–52.e13. Epub 2018/08/11. doi: 10.1016/j.cell.2018.07.033 30096313; PubMed Central PMCID: PMC6102396.

46. Caskey M, Klein F, Lorenzi JC, Seaman MS, West AP Jr., Buckley N, et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature. 2015;522(7557):487–91. Epub 2015/04/10. doi: 10.1038/nature14411 25855300; PubMed Central PMCID: PMC4890714.

47. Fong RH, Banik SS, Mattia K, Barnes T, Tucker D, Liss N, et al. Exposure of epitope residues on the outer face of the chikungunya virus envelope trimer determines antibody neutralizing efficacy. Journal of virology. 2014;88(24):14364–79. Epub 2014/10/03. doi: 10.1128/JVI.01943-14 25275138; PubMed Central PMCID: PMC4249124.

48. Kuhn RJ, Dowd KA, Beth Post C, Pierson TC. Shake, rattle, and roll: Impact of the dynamics of flavivirus particles on their interactions with the host. Virology. 2015;479–480:508–17. Epub 2015/04/04. doi: 10.1016/j.virol.2015.03.025 25835729; PubMed Central PMCID: PMC4900690.

49. Fox JM, Roy V, Gunn BM, Huang L, Edeling MA, Mack M, et al. Optimal therapeutic activity of monoclonal antibodies against chikungunya virus requires Fc-FcgammaR interaction on monocytes. Science immunology. 2019;4(32). Epub 2019/02/24. doi: 10.1126/sciimmunol.aav5062 30796092; PubMed Central PMCID: PMC6698136.

50. Robbie GJ, Criste R, Dall'acqua WF, Jensen K, Patel NK, Losonsky GA, et al. A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob Agents Chemother. 2013;57(12):6147–53. Epub 2013/10/02. doi: 10.1128/AAC.01285-13 24080653; PubMed Central PMCID: PMC3837853.

51. Wec AZ, Nyakatura EK, Herbert AS, Howell KA, Holtsberg FW, Bakken RR, et al. A "Trojan horse" bispecific-antibody strategy for broad protection against ebolaviruses. Science (New York, NY). 2016;354(6310):350–4. Epub 2016/09/10. doi: 10.1126/science.aag3267 27608667.

52. Whelan SP, Ball LA, Barr JN, Wertz GT. Efficient recovery of infectious vesicular stomatitis virus entirely from cDNA clones. Proceedings of the National Academy of Sciences of the United States of America. 1995;92(18):8388–92. Epub 1995/08/29. doi: 10.1073/pnas.92.18.8388 7667300; PubMed Central PMCID: PMC41162.

53. Zhang K. Gctf: Real-time CTF determination and correction. Journal of structural biology. 2016;193(1):1–12. Epub 2015/11/26. doi: 10.1016/j.jsb.2015.11.003 26592709; PubMed Central PMCID: PMC4711343.

54. Voss NR, Yoshioka CK, Radermacher M, Potter CS, Carragher B. DoG Picker and TiltPicker: software tools to facilitate particle selection in single particle electron microscopy. Journal of structural biology. 2009;166(2):205–13. Epub 2009/04/18. doi: 10.1016/j.jsb.2009.01.004 19374019; PubMed Central PMCID: PMC2768396.

55. Scheres SH. RELION: implementation of a Bayesian approach to cryo-EM structure determination. Journal of structural biology. 2012;180(3):519–30. Epub 2012/09/25. doi: 10.1016/j.jsb.2012.09.006 23000701; PubMed Central PMCID: PMC3690530.