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Why Does the Molecular Structure of Broadly Neutralizing Monoclonal Antibodies Isolated from Individuals Infected with HIV-1 not Inform the Rational Design of an HIV-1 Vaccine?

CNRS, UMR7242 - Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg (IREBS), Université de Strasbourg, Illkirch 67400, France

Special Issues: Overcoming the barriers that impede HIV vaccine development and testing

It is commonly assumed that neutralizing Mabs that bind to the HIV-1 Env glycoprotein are more specific reagents than anti-HIV-1 polyclonal antisera and that knowledge of the structure of these Mabs facilitates the rational design of effective HIV-1 vaccine immunogens. However, after more than ten years of unsuccessful experimentation using the structure-based reverse vaccinology approach, it is now evident that it is not possible to infer from the structure of neutralizing Mabs which HIV immunogens induced their formation nor which vaccine immunogens will elicit similar Abs in an immunized host. The use of Mabs for developing an HIV-1 vaccine was counterproductive because it overlooked the fact that the apparent specificity of a Mab very much depends on the selection procedure used to obtain it and also did not take into account that an antibody is never monospecific for a single epitope but is always polyspecific for many epitopes. When the rationale of the proponents of the unsuccessful rational design strategy is analyzed, it appears that investigators who claim they are designing a vaccine immunogen are only improving the binding reactivity of a single epitope-paratope pair and are not actually designing an immunogen able to generate protective antibodies. The task of a designer consists in imagining what type of immunogen is likely to elicit a protective immune response but in the absence of knowledge regarding which features of the immune system are responsible for producing a functional neutralizing activity in antibodies, it is not feasible to intentionally optimize a potential immunogen candidate in order to obtain the desired outcome. The only available option is actually to test possible solutions by trial-and-error experiments until the preset goal is perhaps attained. Rational design and empirical approaches in HIV vaccine research should thus not be opposed as alternative options since empirical testing is an integral part of a so-called design strategy.
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References

1. Esparza J (2013) What has 30 years of HIV research taught us? Vaccines 1: 513-526.    

2. Van Regenmortel MHV, Andrieu J-M, Dimitrov DS, et al. (2014) Paradigm Changes and the Future of HIV Vaccine Research: A Summary of a Workshop Held in Baltimore on 20 November 2013. J AIDS Clin Res 5: 3.

3. Burton DR (2002) Antibodies, viruses and vaccines. Nat Rev Immunol 2: 706-713.    

4. Van Regenmortel MHV (2014) An outdated notion of antibody specificity is one of the major detrimental assumptions of the structure-based reverse vaccinology paradigm, which prevented it from developing an effective HIV-1 vaccine. Front Immunol 5: 593. doi: 10.3389/fimmun.1014.00593.

5. Dimitrov DS (2010) Therapeutic antibodies, vaccines and antibodyomes. MAbs 2: 347-356.

6. Van Regenmortel MHV (2012) Basic research in HIV vaccinology is hampered by reductionist thinking. Front Immunol 3: 194.

7. Richards FF, Konigsberg WH, Rosenstein RW, et al. (1975) On the specificity of antibodies. Science 187: 130-137.    

8. Van Regenmortel MHV (2014) Specificity, polyspecificity, and heterospecificity of antibody-antigen recognition. J Mol Recognit 27: 627-639.    

9. Vijh-Warrier S, Pinter A, Honnen WJ, et al. (1996) Synergistic neutralization of human immunodeficiency virus type 1 by a chimpanzee monoclonal antibody against the V2 domain of gp120 in combination with monoclonal antibodies against the V3 loop and the CD4-binding site. J Virol 70: 4466-4475.

10. Li A, Katinger H, Posner MR, et al. (1998) Synergistic neutralization of simian-human immunodeficiency virus SHIV-vpu+ by triple and quadruple combinations of human monoclonal antibodies and high-titer anti-human immunodeficiency virus type 1 immunoglobulins. J Virol 72: 3235-3240.

11. Mascola JR, Louder MK, VanCott TC, et al. (1997) Potent and synergistic neutralization of human immunodeficiency virus (HIV) type 1 primary isolates by hyperimmune anti-HIV immunoglobulin combined with monoclonal antibodies 2F5 and 2G12. J Virol 71: 7198-7206.

12. Li A, Baba TW, Sodroski J, et al. (1997) Synergistic neutralization of a chimeric SIV/HIV type 1 virus with combinations of human anti-HIV type 1 envelope monoclonal antibodies or hyperimmune globulins. AIDS Res Hum Retroviruses 13: 647-656.    

13. Mascola JR, Haynes BF (2013) HIV-1 neutralizing antibodies: understanding nature's pathways. Immunol Rev 254: 225-244.    

14. Nabel GJ, Kwong PD, Mascola JR (2011) Progress in the rational design of an AIDS vaccine. Phil Trans Roy Soc London B Biol Sci 366: 2759-2765.    

15. Schiller J, Chackerian B (2014) Why HIV virions have low numbers of envelope spikes: implications for vaccine development. PloS Pathog 10: e1004254.

16. Wardemann H, Yurasov S, Schaefer A, et al. (2003) Predominant autoantibody production by early human B cell precursors. Science 301: 1374-1377.    

17. Verkoczy L, Diaz M (2014) Autoreactivity in HIV-1 broadly neutralizing antibodies: implications for their function and induction by vaccination. Curr Opin HIV AIDS 9: 224-234.    

18. Poignard P, Moulard M, Golez E, et al. (2003) Heterogeneity of envelope molecules expressed on primary human immunodeficiency virus type 1 particles as probed by the binding of neutralizing and non neutralizing antibodies. J Virol 77: 353-365.    

19. Moore PL, Crooks ET, Porter L, et al. (2006) Nature of nonfunctional envelope proteins on the surface of human immunodeficiency virus type 1. J Virol 80: 2515-2528.    

20. Liu J, Bartesaghi A, Borgnia MJ, et al. (2008) Molecular architecture of native HIV-1 gp120 trimers. Nature 455: 109-113.    

21. Schief WR, Ban YE, Stamatatos L (2009) Challenges for structure-based HIV vaccine design. Curr Opin HIV AIDS 4: 431-440.    

22. Van Regenmortel MHV (1966) Plant virus serology. Adv Virus Res 12: 207-271.

23. Pancera M, McLellan JS, Wu X, et al. (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.    

24. Van Regenmortel MHV (1992) The conformational specificity of viral epitopes. FEMS Microbiol Lett 100: 483-487.    

25. McElrath MJ, Haynes BF (2010) Induction of immunity to human immunodeficiency virus type-1 by vaccination. Immunity 33: 542-554.    

26. Burton DR, Desrosiers RC, Doms R, et al. (2004) HIV vaccine design and the neutralizing antibody problem. Nat Immunol 5: 233-236.    

27. Corti D, Lanzavecchia A (2013) Broadly neutralizing antiviral antibodies. Ann Rev Immunol 31: 705-42.    

28. Walker LM, Phogat SK, Chan-Hui PY, et al. (2009) Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 326: 285-289.    

29. Zhou T, Georgiev I, Wu X et al. (2010) Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 329: 811-817.    

30. Sattentau QJ, McMichael AJ (2010) New templates for HIV-1 antibody-based vaccine design. F1000 Biol.Rep. 2: 60.

31. Lewis GK (2010) Challenges of antibody-mediated protection against HIV-1. Exp Rev Vaccines 9: 683-687.    

32. Yu L, Guan Y (2014) Immunologic basis for long HCDR3s in broadly neutralizing antibodies against HIV-1. Front Immunol 5: 250.

33. Stanfield RL, Gorny MK, Williams C, et al. (2004) Structural rationale for the broad neutralization of HIV-1 by human monoclonal antibody 447- 52D. Structure 12: 193-204.    

34. Briney BS, Willis JR, Crowe JE (2012) Human peripheral blood antibodies with long HCDR3s are established primarily at original recombination using a limited subset of germline genes. PLoS ONE 7: e36750.    

35. Ackerman M, Alter G (2013) Mapping the journey to an HIV vaccine. N Engl J Med 369: 389-391.    

36. Klasse PJ, Sanders RW, Cerutti A, et al. (2012) How can HIV-type-1-Env immunogenicity be improved to facilitate antibody-based vaccine development? AIDS Res Hum Retroviruses 28: 1-15.    

37. Bunnik EM, van Gils MJ, Lobbrecht MS, et al. (2009) Changing sensitivity to broadly neutralizing antibodies b12, 2G12, 2F5, and 4E10 of primary subtype B human immunodeficiency virus type 1 variants in the natural course of infection. Virology 390: 348-355.    

38. Berzofsky JA (1985) Intrinsic and extrinsic factors in protein antigenic structure. Science 229: 932-940.    

39. Kunik V, Ofran Y (2013) The indistinguishability of epitopes from protein surface is explained by the distinct binding preferences of each of the six antigen-binding loops. Protein Eng Des Sel 26: 599-609.    

40. Sela-Culang I, Kunik V, Ofran Y (2013) The structural basis of antibody-antigen recognition. Front Immunol 4: 302.

41. Van Regenmortel MHV (2011) Limitations to the structure-based design of HIV-1 vaccine immunogens. J Mol Recognit 24: 741-753.    

42. Van Regenmortel MHV (2012) Requirements for empirical immunogenicity trials, rather than structure-based design, for developing an effective HIV vaccine. Arch Virol 157: 1-20.    

43. Dimitrov JD, Pashov AD, Vassilev TL (2012) Antibody specificity what does it matter ? Adv Exp Biol Med 750: 213-226.    

44. Notkins AL (2004) Polyreactivity of antibody molecules. Trends Immunol 25: 174-9.    

45. Wucherpfennig KW, Allen PM, Celada F, et al. (2007) Polyspecificity of T cell and B cell receptor recognition. Semin Immunol 19: 216-24.    

46. Eisen HN, Chakraborty AK (2010) Evolving concepts of specificity inimmune reactions. Proc Natl Acad Sci USA 107: 22373-22380.    

47. Mariuzza RA (2006) Multiple paths to multispecificity. Immunity 24: 359-361.    

48. Bramwell VW, Perrie Y (2005) The rational design of vaccines. Drug Discov Today 10: 1527-1534.    

49. Douek DC, Kwong PD, Nabel GJ (2006) The rational design of an AIDS vaccine. Cell 124: 677-681.    

50. D'Argenio DA, Wilson CB (2010) A decade of vaccines: integrating immunology and vaccinology for rational vaccine design. Immunity 33: 437-440.    

51. Walker LM, Burton DR (2010) Rational antibody-based HIV-1 vaccine design: current approaches and future directions. Curr Opin Immunol 22: 358-366.    

52. Burton DR (2010) Scaffolding to build a rational vaccine design strategy. Proc Natl Acad Sci USA 107: 17859-17860.    

53. Van Regenmortel MHV (2007) The rational design of biological complexity: a deceptive metaphor. Proteomics 7: 965-975.    

54. Kuntz ID (1992) Structure-based strategies for drug design and discovery. Science 257: 1078-1082.    

55. Wu X, Yang ZY, Li Y, et al. (2010) Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 329: 856-861.    

56. Diskin R, Scheid JF, Marcovecchio PM, et al. (2011) Increasing the potency and breadth of an HIV antibody by using structure-based rational design. Science 334: 1289-1293.    

57. Correia B, Bates JT, Loomis RJ, et al. (2014) Proof of principle for epitope-focused vaccine design. Nature 507: 201-206.    

58. Bunge M (2003) Philosophical Dictionary. Amherst, NY: Promotheus Books.

59. Karlsson-Hedestam GB, Fouchier RA, Phogat S, et al. (2008) The challenges of eliciting neutralizing antibodies to HIV-1 and to influenza virus. Nat Rev Microbiol 6: 143-155.    

60. Haynes BF, Kelsoe G, Harrison SC, et al. (2012) B-cell-lineage immunogen design in vaccine development with HIV-1 as a case study. Nat Biotech 30: 423-433.    

61. Moore PL, Gray ES, Wibmer CK, et al. (2012) Evolution of an HIV glycan-dependent broadly neutralizing antibody epitope through immune escape. Nat Med 18: 1688-1692.    

62. Klein F, Diskin R, Scheid JF, et al. (2013) Somatic mutations of the immunoglobulin framework are generally required for broad and potent HIV-1 neutralization. Cell 153: 126-138.    

63. Liao HX, Lynch R, Zhou T, et al. (2013) Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature 496: 469-476.    

64. Verkoczy L, Kelsoe G, Haynes BF, et al. (2014) HIV-1 envelope gp41 broadly neutralizing antibodies: hurdles for vaccine development. PLoS Pathog 10: e 1004073.

65. West AP Jr, Scharf L, Scheid JF, et al. (2014) Structural insights on the role of antibodies in HIV-1 vaccine and therapy. Cell 156: 633-648.    

66. Doria-Rose NA, Schramm CA, Gorman J, et al. (2014) Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies. Nature 509: 55-62.    

67 Prabakaran P, Chen W, Dimitrov DS (2014) The antibody germline/maturation hypothesis, elicitation of broadly neutralizing antibodies against HIV-1 and cord blood IgM repertoires. Front Immunol 5: 398.

Copyright Info: © 2015, Marc H V Van Regenmortel, licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

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