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Antibody-based Protection Against HIV Infection

  • Brian Moldt
  • Dennis R. Burton
Chapter

Abstract

The hu-PBL-SCID mouse was among the first animal models to clearly demonstrate the ability of neutralizing antibodies to protect against the HIV challenge in vivo. Conclusions from these early experiments have largely been borne out in more recent studies performed with newer humanized mice models such as Rag-hu, NSG-hu, and BLT that show improved mimicry of human infections. In addition to passive transfer, protection has also been demonstrated for neutralizing antibodies delivered by viral vectors, i.e., vectored immunoprophylaxis. In addition, whereas early studies in hu-PBL-SCID mice showed antibodies to be relatively ineffective in control of established HIV infection because of neutralization escape, recent studies in newer models with cocktails of more potent neutralizing antibodies have shown effective control of virus replication and suppression of escape.

Keywords

Antibody Neutralization bNAbs HIV Animal models Passive transfer Immunoprophylaxis Therapy 

Notes

Acknowledgments

We thank Christina Corbaci for help with graphic design. The authors acknowledge the financial support of the National Institute of Allergy and Infectious Diseases, the Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery; the International AIDS Vaccine Initiative; the Ragon Institute of MGH, MIT, and Harvard; and the Lundbeck Foundation.

References

  1. 1.
    Amanna IJ, Slifka MK. Contributions of humoral and cellular immunity to vaccine-induced protection in humans. Virology. 2011;411(2):206–15. (PubMed PMID: 21216425. Pubmed Central PMCID: Journal—In Process. Epub 2011/01/11. eng.).CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    Plotkin SA. Correlates of protection induced by vaccination. Clin Vaccine Immunol. 2010;17(7):1055–65. (PubMed PMID: 20463105. Pubmed Central PMCID: 2897268. Epub 2010/05/14. eng.).CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Burton DR, Ahmed R, Barouch DH, Butera ST, Crotty S, Godzik A, et al. A blueprint for HIV vaccine discovery. Cell host microbe. 2012;12(4):396–407. (PubMed PMID: 23084910. Pubmed Central PMCID: 3513329).CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Virgin HW, Walker BD. Immunology and the elusive AIDS vaccine. Nature. 2010;464(7286):224–31. (PubMed PMID: 20220841. Pubmed Central PMCID: Journal—In Process. Epub 2010/03/12. eng.).CrossRefPubMedGoogle Scholar
  5. 5.
    Fauci AS, Johnston MI, Dieffenbach CW, Burton DR, Hammer SM, Hoxie JA, et al. HIV vaccine research: the way forward. Science. 2008;321(5888):530–2. (PubMed PMID: 18653883. Epub 2008/07/26. eng.).CrossRefPubMedGoogle Scholar
  6. 6.
    Walker LM, Phogat SK, Chan-Hui PY, Wagner D, Phung P, Goss JL, et al. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science. 2009;326(5950):285–9. (PubMed PMID: 19729618. Pubmed Central PMCID: 2916884. Epub 2009/09/05. Eng).CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Walker LM, Huber M, Doores KJ, Falkowska E, Pejchal R, Julien JP, et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature. 2011;477(7365):466–70.CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Wu X, Yang ZY, Li Y, Hogerkorp CM, Schief WR, Seaman MS, et al. Rational design of envelope surface identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science. 2010;329(5993):856–61. (Pubmed Central PMCID: 2965066).CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Huang J, Ofek G, Laub L, Louder MK, Doria-Rose NA, Longo NS, et al. Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature. 2012; In Press.Google Scholar
  10. 10.
    Scheid JF, Mouquet H, Ueberheide B, Diskin R, Klein F, Olivera TYK, et al. Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science. 2011;333(6049):1633–7.CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Bonsignori M, Hwang KK, Chen X, Tsao CY, Morris L, Gray E, et al. 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. 2011;85(19):9998–10009. (PubMed PMID: 21795340. Epub 2011/07/29. Eng.).CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Liao HX, Lynch R, Zhou TQ, Gao F, Alam SM, Boyd SD, et al. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature. 2013;496(7446):469–76. (PubMed PMID: WOS:000317984400034. English).CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Moldt B, Rakasz EG, Schultz N, Chan-Hui PY, Swiderek K, Weisgrau KL, et al. Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo. Proc Natl Acad Sci U S A. 2012;109(46):18921–5. (PubMed PMID: WOS:000311576300062. English).CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Parren PW, Marx PA, Hessell AJ, Luckay A, Harouse J, Cheng-Mayer C, et al. Antibody protects macaques against vaginal challenge with a pathogenic R5 simian/human immunodeficiency virus at serum levels giving complete neutralization in vitro. J Virol. 2001;75(17):8340–7. (PubMed PMID: 11483779).CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Mascola JR, Stiegler G, VanCott TC, Katinger H, Carpenter CB, Hanson CE, et al. Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat Med. 2000;6(2):207–10. (PubMed PMID: 10655111).CrossRefPubMedGoogle Scholar
  16. 16.
    Hessell AJ, Rakasz EG, Poignard P, Hangartner L, Landucci G, Forthal DN, et al. Broadly neutralizing human anti-HIV antibody 2G12 is effective in protection against mucosal SHIV challenge even at low serum neutralizing titers. PLoS Pathog. 2009;5(5):e1000433. (PubMed PMID: 19436712. Pubmed Central PMCID: 2674935. Epub 2009/05/14. eng).CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Hessell AJ, Rakasz EG, Tehrani DM, Huber M, Landucci G, Forthal DN, et al. Broadly neutralizing monoclonal antibodies 2F5 and 4E10 directed against the human immunodeficiency virus type 1 gp41 membrane-proximal external region protect against mucosal challenge by simian-human immunodeficiency virus SHIVBa-L. J Virol. 2010;84(3):1302–13. (Pubmed Central PMCID: 2812338).CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Mascola JR, Lewis MG, Stiegler G, Harris D, VanCott TC, Hayes D, et al. Protection of macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies. J Virol. 1999;73(5):4009–18. (PubMed PMID: 10196297).PubMedCentralPubMedGoogle Scholar
  19. 19.
    Safrit JT, Fung MSC, Andrews CA, Braun DG, Sun WNC, Chang TW, et al. Hu-Pbl-Scid Mice Can Be Protected from Hiv-1 Infection by Passive Transfer of Monoclonal-Antibody to the Principal Neutralizing Determinant of Envelope Gp120. AIDS. 1993;7(1):15–21. (PubMed PMID: WOS:A1993KG97000002. English).CrossRefPubMedGoogle Scholar
  20. 20.
    Emini EA, Schleif WA, Nunberg JH, Conley AJ, Eda Y, Tokiyoshi S, et al. Prevention of Hiv-1 Infection in chimpanzees by Gp120 V3 domain-specific monoclonal-antibody. Nature. 1992;355(6362):728–30. (PubMed PMID: WOS:A1992HE60400064. English).CrossRefPubMedGoogle Scholar
  21. 21.
    Gauduin MC, Safrit JT, Weir R, Fung MSC, Koup RA. Preexposure and postexposure protection against human-immunodeficiency-virus type-1 infection mediated by a monoclonal-antibody. J Infect Dis. 1995;171(5):1203–9. (PubMed PMID: WOS:A1995QU64000018. English).CrossRefPubMedGoogle Scholar
  22. 22.
    Gauduin MC, Parren PW, Weir R, Barbas CF, 3rd, Burton DR, Koup RA. Passive immunization with a human monoclonal antibody protects hu-PBL-SCID mice against challenge by primary isolates of HIV-1. Nat Med. 1997;3(12):1389–93. (PubMed PMID: 9396610).CrossRefPubMedGoogle Scholar
  23. 23.
    Parren PW, Ditzel HJ, Gulizia RJ, Binley JM, Barbas CF, 3rd, Burton DR, et al. Protection against HIV-1 infection in hu-PBL-SCID mice by passive immunization with a neutralizing human monoclonal antibody against the gp120 CD4-binding site. AIDS. 1995;9(6):F1–6. (PubMed PMID: 7662189).CrossRefPubMedGoogle Scholar
  24. 24.
    Haase AT. Early events in sexual transmission of HIV and SIV and opportunities for interventions. Annu Rev Med. 2011;62:127–39. (PubMed PMID: 21054171. Pubmed Central PMCID: Journal—In Process. Epub 2010/11/09. eng.).CrossRefPubMedGoogle Scholar
  25. 25.
    Haase AT. Targeting early infection to prevent HIV-1 mucosal transmission. Nature. 2010;464(7286):217–23. (PubMed PMID: 20220840. Pubmed Central PMCID: Journal—In Process. Epub 2010/03/12. eng.).CrossRefPubMedGoogle Scholar
  26. 26.
    D’cruz OJ, Uckun FM. Limitations of the human-PBL-SCID mouse model for vaginal transmission of HIV-1. Am J Reprod Immunol. 2007;57(5):353–60. (PubMed PMID: WOS:000245674000002. English).CrossRefPubMedGoogle Scholar
  27. 27.
    Mosier DE, Gulizia RJ, Baird SM, Wilson DB. Transfer of a functional human immune-system to mice with severe combined immunodeficiency. Nature. 1988;335(6187):256–9. (PubMed PMID: WOS:A1988Q047700061. English).CrossRefPubMedGoogle Scholar
  28. 28.
    Mosier DE, Gulizia RJ, Baird SM, Wilson DB, Spector DH, Spector SA. Human immunodeficiency virus infection of human-PBL-SCID mice. Science. 1991;251(4995):791–4. (PubMed PMID: 1990441).CrossRefPubMedGoogle Scholar
  29. 29.
    Sun ZF, Denton PW, Estes JD, Othieno FA, Wei BL, Wege AK, et al. Intrarectal transmission, systemic infection, and CD4(+) T cell depletion in humanized mice infected with HIV-1. J Exp Med. 2007;204(4):705–14. (PubMed PMID: WOS:000245920600003. English).CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Stoddart CA, Maidji E, Galkina SA, Kosikova G, Rivera JM, Moreno ME, et al. Superior human leukocyte reconstitution and susceptibility to vaginal HIV transmission in humanized NOD-scid IL-2R gamma(-/-) (NSG) BLT mice. Virology. 2011;417(1):154–60. (PubMed PMID: WOS:000293820300018. English).CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Denton PW, Garcia JV. Mucosal HIV-1 transmission and prevention strategies in BLT humanized mice. Trends Microbiol. 2012;20(6):268–74. (PubMed PMID: WOS:000305502500003. English).CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    Balazs AB, Chen J, Hong CM, Rao DS, Yang L, Baltimore D. Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature. 2012;481(7379):81–4. (PubMed PMID: 22139420. Pubmed Central PMCID: 3253190. Epub 2011/12/06. eng).CrossRefGoogle Scholar
  33. 33.
    Klein F, Halper-Stromberg A, Horwitz JA, Gruell H, Scheid JF, Bournazos S, et al. HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature. 2012;492(7427):118–22. (PubMed PMID: 23103874).CrossRefPubMedGoogle Scholar
  34. 34.
    Conley AJ, Kessler JA, II, Boots LJ, McKenna PM, Schleif WA, Emini EA, et al. The consequence of passive administration of an anti-human immunodeficiency virus type 1 neutralizing monoclonal antibody before challenge of chimpanzees with a primary virus isolate. J Virol. 1996;70(10):6751–8. (PubMed PMID: 8794312).PubMedCentralPubMedGoogle Scholar
  35. 35.
    Muster T, Steindl F, Purtscher M, Trkola A, Klima A, Himmler G, et al. A conserved neutralizing epitope on gp41 of human immunodeficiency virus type 1. J Virol. 1993;67(11):6642–7. (PubMed PMID: 7692082).PubMedCentralPubMedGoogle Scholar
  36. 36.
    Veselinovic M, Neff CP, Mulder LR, Akkina R. Topical gel formulation of broadly neutralizing anti-HIV-1 monoclonal antibody VRC01 confers protection against HIV-1 vaginal challenge in a humanized mouse model. Virology. 2012;432(2):505–10. (PubMed PMID: 22832125. Pubmed Central PMCID: 3652800).CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Hur EM, Patel SN, Shimizu S, Rao DS, Gnanapragasam PN, An DS, et al. Inhibitory effect of HIV-specific neutralizing IgA on mucosal transmission of HIV in humanized mice. Blood. 2012;120(23):4571–82. (PubMed PMID: 23065154. Pubmed Central PMCID: 3512234).CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.
    Watkins JD, Sholukh AM, Mukhtar MM, Siddappa NB, Lakhashe SK, Kim M, et al. Anti-HIV IgA isotypes: differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission. AIDS. 2013;27(9):F13–20. (PubMed PMID: 23775002).CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C, Mansoor LE, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010;329(5996):1168–74. (PubMed PMID: 20643915. Pubmed Central PMCID: 3001187).CrossRefPubMedCentralPubMedGoogle Scholar
  40. 40.
    Shattock RJ, Rosenberg Z. Microbicides: topical prevention against HIV. Cold Spring Harb Perspect Med. 2012;2(2):a007385. (PubMed PMID: 22355798. Pubmed Central PMCID: 3281595).CrossRefPubMedCentralPubMedGoogle Scholar
  41. 41.
    Veazey RS, Shattock RJ, Pope M, Kirijan JC, Jones J, Hu Q, et al. Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120. Nat Med. 2003;9(3):343–6. (PubMed PMID: 12579198).CrossRefPubMedGoogle Scholar
  42. 42.
    Pietzsch J, Gruell H, Bournazos S, Donovan BM, Klein F, Diskin R, et al. A mouse model for HIV-1 entry. Proc Natl Acad Sci U S A. 2012;109(39):15859–64. (PubMed PMID: 23019371. Pubmed Central PMCID: 3465400).CrossRefPubMedCentralPubMedGoogle Scholar
  43. 43.
    Gruell H, Bournazos S, Ravetch JV, Ploss A, Nussenzweig MC, Pietzsch J. Antibody and antiretroviral pre-exposure prophylaxis prevent cervicovaginal HIV-1 infection in a transgenic mouse model. J Virol. 2013. Aug;87(15):8535–44. (PubMed PMID: 23720722).Google Scholar
  44. 44.
    Asokan A, Schaffer DV, Samulski RJ. The AAV vector toolkit: poised at the clinical crossroads. Mol Ther. 2012;20(4):699–708. (PubMed PMID: 22273577. Pubmed Central PMCID: 3321598).CrossRefPubMedCentralPubMedGoogle Scholar
  45. 45.
    Johnson PR, Schnepp BC, Zhang J, Connell MJ, Greene SM, Yuste E, et al. Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys. Nat Med. 2009;15(8):901–6. (PubMed PMID: 19448633. Pubmed Central PMCID: 2723177. Epub 2009/05/19. eng.).CrossRefPubMedCentralPubMedGoogle Scholar
  46. 46.
    Balazs AB, West AP, Jr. Antibody gene transfer for HIV immunoprophylaxis. Nat Immunol. 2013;14(1):1–5. (PubMed PMID: 23238748).CrossRefPubMedGoogle Scholar
  47. 47.
    Balazs AB, Bloom JD, Hong CM, Rao DS, Baltimore D. Broad protection against influenza infection by vectored immunoprophylaxis in mice. Nat Biotechnol. 2013;31(7):647–52. (PubMed PMID: 23728362).CrossRefPubMedCentralPubMedGoogle Scholar
  48. 48.
    Wei X, Decker JM, Wang S, Hui H, Kappes JC, Wu X, et al. Antibody neutralization and escape by HIV-1. Nature. 2003;422(6929):307–12. (PubMed PMID: 12646921).CrossRefPubMedGoogle Scholar
  49. 49.
    Poignard P, Sabbe R, Picchio GR, Wang M, Gulizia RJ, Katinger H, et al. Neutralizing antibodies have limited effects on the control of established HIV-1 infection in vivo. Immunity. 1999;10(4):431–8. (PubMed PMID: 10229186).CrossRefPubMedGoogle Scholar
  50. 50.
    Trkola A, Kuster H, Rusert P, Joos B, Fischer M, Leemann C, et al. Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive transfer of human neutralizing antibodies. Nat Med. 2005;11:615–22. (PubMed PMID: 15880120).CrossRefPubMedGoogle Scholar
  51. 51.
    Diskin R, Klein F, Horwitz JA, Halper-Stromberg A, Sather DN, Marcovecchio PM, et al. Restricting HIV-1 pathways for escape using rationally designed anti-HIV-1 antibodies. J Exp Med. 2013;210(6):1235–49. (PubMed PMID: 23712429. Pubmed Central PMCID: 3674693).CrossRefPubMedCentralPubMedGoogle Scholar
  52. 52.
    Horwitz JA, Halper-Stromberg A, Mouquet H, Gitlin AD, Tretiakova A, Eisenreich TR, et al. HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice. Proc Natl Acad Sci U S A. 2013.Oct 8;110(41):16538–43. (PubMed PMID: 24043801).Google Scholar
  53. 53.
    Nelson AL, Dhimolea E, Reichert JM. Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov. 2010;9(10):767–74. (PubMed PMID: 20811384).CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Immunology and Microbial Science, International AIDS Vaccine Initiative Neutralizing Antibody Center, and Center for HIV/AIDS Vaccine Immunology and Immunogen DiscoveryThe Scripps Research InstituteLa JollaUSA
  2. 2.Ragon Institute of Massachusetts General HospitalMassachusetts Institute of Technology, and Harvard UniversityBostonUSA

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