AAV-Delivered Antibody Mediates Significant Protective Effects against SIVmac239 Challenge in the Absence of Neutralizing Activity

English version České info

AAV-mediated antibody delivery represents a promising alternative to classical vaccine approaches for the prevention of HIV/AIDS in humans. We used recombinant adeno-associated viral vectors (rAAV) as gene carrier to deliver anti-SIV (simian immunodeficiency virus) antibodies to monkeys. This non-classical immunization approach is independent of the host immune system and the AAV-transferred gene into muscle cells produces antibodies with known specificities. Our goal was to determine what serum levels of delivered antibodies can be achieved by using two different vector strategies, whether the delivered antibodies provoke an immune response, and to what degree the delivered non-neutralizing antibodies have the ability to protect against SIV virus challenge. This approach allowed for sustained levels of delivered antibodies in serum and exhibited significant protective effects against highly pathogenic SIVmac239 challenge. However, immune responses limited the concentration of circulating antibodies that could be achieved. This problem will need to be understood and overcome for the promise of this approach to be effectively realized.

Vyšlo v časopise: AAV-Delivered Antibody Mediates Significant Protective Effects against SIVmac239 Challenge in the Absence of Neutralizing Activity. PLoS Pathog 11(8): e32767. doi:10.1371/journal.ppat.1005090
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005090

Souhrn

Zdroje

1. Desrosiers RC (1999) Strategies used by human immunodeficiency virus that allow persistent viral replication. Nat Med 5: 723–725. 10395309

2. Evans DT, Desrosiers RC (2001) Immune evasion strategies of the primate lentiviruses. Immunol Rev 183: 141–158. 11782254

3. Lewis AD, Chen R, Montefiori DC, Johnson PR, Clark KR (2002) Generation of neutralizing activity against human immunodeficiency virus type 1 in serum by antibody gene transfer. J Virol 76: 8769–8775. 12163597

4. Johnson PR, Schnepp BC, Zhang J, Connell MJ, Greene SM, et al. (2009) Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys. Nat Med 15: 901–906. doi: 10.1038/nm.1967 19448633

5. Balazs AB, Chen J, Hong CM, Rao DS, Yang L, et al. (2012) Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature 481: 81–84.

6. Schnepp BC, Johnson PR (2014) Adeno-associated virus delivery of broadly neutralizing antibodies. Curr Opin HIV AIDS 9: 250–256. doi: 10.1097/COH.0000000000000056 24638019

7. Gardner MR, Kattenhorn LM, Kondur HR, von Schaewen M, Dorfman T, et al. (2015) AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature 519: 87–91. doi: 10.1038/nature14264 25707797

8. Fang J, Qian JJ, Yi S, Harding TC, Tu GH, et al. (2005) Stable antibody expression at therapeutic levels using the 2A peptide. Nat Biotechnol 23: 584–590. 15834403

9. Rivera VM, Gao GP, Grant RL, Schnell MA, Zoltick PW, et al. (2005) Long-term pharmacologically regulated expression of erythropoietin in primates following AAV-mediated gene transfer. Blood 105: 1424–1430. 15507527

10. Wang D, Zhong L, Nahid MA, Gao G (2014) The potential of adeno-associated viral vectors for gene delivery to muscle tissue. Expert Opin Drug Deliv 11: 345–364. doi: 10.1517/17425247.2014.871258 24386892

11. Gaudet D, Methot J, Dery S, Brisson D, Essiembre C, et al. (2013) Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial. Gene Ther 20: 361–369. doi: 10.1038/gt.2012.43 22717743

12. Bowles DE, McPhee SW, Li C, Gray SJ, Samulski JJ, et al. (2012) Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Mol Ther 20: 443–455. doi: 10.1038/mt.2011.237 22068425

13. Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, et al. (2011) Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 365: 2357–2365. doi: 10.1056/NEJMoa1108046 22149959

14. Kwong PD, Mascola JR, Nabel GJ (2013) Broadly neutralizing antibodies and the search for an HIV-1 vaccine: the end of the beginning. Nat Rev Immunol 13: 693–701. doi: 10.1038/nri3516 23969737

15. Horwitz JA, Halper-Stromberg A, Mouquet H, Gitlin AD, Tretiakova A, et al. (2013) 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 110: 16538–16543. doi: 10.1073/pnas.1315295110 24043801

16. Klein F, Mouquet H, Dosenovic P, Scheid JF, Scharf L, et al. (2013) Antibodies in HIV-1 vaccine development and therapy. Science 341: 1199–1204. doi: 10.1126/science.1241144 24031012

17. Corti D, Lanzavecchia A (2013) Broadly neutralizing antiviral antibodies. Annu Rev Immunol 31: 705–742. doi: 10.1146/annurev-immunol-032712-095916 23330954

18. Klein F, Halper-Stromberg A, Horwitz JA, Gruell H, Scheid JF, et al. (2012) HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature 492: 118–122. doi: 10.1038/nature11604 23103874

19. Burton DR, Poignard P, Stanfield RL, Wilson IA (2012) Broadly neutralizing antibodies present new prospects to counter highly antigenically diverse viruses. Science 337: 183–186. doi: 10.1126/science.1225416 22798606

20. Pejchal R, Doores KJ, Walker LM, Khayat R, Huang PS, et al. (2011) A potent and broad neutralizing antibody recognizes and penetrates the HIV glycan shield. Science 334: 1097–1103. doi: 10.1126/science.1213256 21998254

21. Walker LM, Huber M, Doores KJ, Falkowska E, Pejchal R, et al. (2011) Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477: 466–470. doi: 10.1038/nature10373 21849977

22. Daya S, Berns KI (2008) Gene therapy using adeno-associated virus vectors. Clin Microbiol Rev 21: 583–593. doi: 10.1128/CMR.00008-08 18854481

23. Wang Z, Ma HI, Li J, Sun L, Zhang J, et al. (2003) Rapid and highly efficient transduction by double-stranded adeno-associated virus vectors in vitro and in vivo. Gene Ther 10: 2105–2111. 14625564

24. Gao GP, Lu Y, Sun X, Johnston J, Calcedo R, et al. (2006) High-level transgene expression in nonhuman primate liver with novel adeno-associated virus serotypes containing self-complementary genomes. J Virol 80: 6192–6194. 16731960

25. McCarty DM (2008) Self-complementary AAV vectors; advances and applications. Mol Ther 16: 1648–1656. doi: 10.1038/mt.2008.171 18682697

26. Johnson WE, Sanford H, Schwall L, Burton DR, Parren PW, et al. (2003) Assorted mutations in the envelope gene of simian immunodeficiency virus lead to loss of neutralization resistance against antibodies representing a broad spectrum of specificities. J Virol 77: 9993–10003. 12941910

27. Lewis MG, Bellah S, McKinnon K, Yalley-Ogunro J, Zack PM, et al. (1994) Titration and characterization of two rhesus-derived SIVmac challenge stocks. AIDS Res Hum Retroviruses 10: 213–220. 8198874

28. Lifson JD, Rossio JL, Piatak M Jr., Parks T, Li L, et al. (2001) Role of CD8(+) lymphocytes in control of simian immunodeficiency virus infection and resistance to rechallenge after transient early antiretroviral treatment. J Virol 75: 10187–10199. 11581387

29. Jia B, Ng SK, DeGottardi MQ, Piatak M, Yuste E, et al. (2009) Immunization with single-cycle SIV significantly reduces viral loads after an intravenous challenge with SIV(mac)239. PLoS Pathog 5: e1000272. doi: 10.1371/journal.ppat.1000272 19165322

30. Bilello JP, Manrique JM, Shin YC, Lauer W, Li W, et al. (2011) Vaccine protection against simian immunodeficiency virus in monkeys using recombinant gamma-2 herpesvirus. J Virol 85: 12708–12720. doi: 10.1128/JVI.00865-11 21900170

31. Evans DT, Bricker JE, Sanford HB, Lang S, Carville A, et al. (2005) Immunization of macaques with single-cycle simian immunodeficiency virus (SIV) stimulates diverse virus-specific immune responses and reduces viral loads after challenge with SIVmac239. J Virol 79: 7707–7720. 15919923

32. Murphy CG, Lucas WT, Means RE, Czajak S, Hale CL, et al. (2000) Vaccine protection against simian immunodeficiency virus by recombinant strains of herpes simplex virus. J Virol 74: 7745–7754. 10933680

33. Kaur A, Sanford HB, Garry D, Lang S, Klumpp SA, et al. (2007) Ability of herpes simplex virus vectors to boost immune responses to DNA vectors and to protect against challenge by simian immunodeficiency virus. Virology 357: 199–214. 16962628

34. Horton H, Vogel TU, Carter DK, Vielhuber K, Fuller DH, et al. (2002) Immunization of rhesus macaques with a DNA prime/modified vaccinia virus Ankara boost regimen induces broad simian immunodeficiency virus (SIV)-specific T-cell responses and reduces initial viral replication but does not prevent disease progression following challenge with pathogenic SIVmac239. J Virol 76: 7187–7202. 12072518

35. Casimiro DR, Wang F, Schleif WA, Liang X, Zhang ZQ, et al. (2005) Attenuation of simian immunodeficiency virus SIVmac239 infection by prophylactic immunization with dna and recombinant adenoviral vaccine vectors expressing Gag. J Virol 79: 15547–15555. 16306625

36. Alpert MD, Heyer LN, Williams DE, Harvey JD, Greenough T, et al. (2012) A novel assay for antibody-dependent cell-mediated cytotoxicity against HIV-1- or SIV-infected cells reveals incomplete overlap with antibodies measured by neutralization and binding assays. J Virol 86: 12039–12052. doi: 10.1128/JVI.01650-12 22933282

37. Buchlis G, Podsakoff GM, Radu A, Hawk SM, Flake AW, et al. (2012) Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer. Blood 119: 3038–3041. doi: 10.1182/blood-2011-09-382317 22271447

38. Kaeppel C, Beattie SG, Fronza R, van Logtenstein R, Salmon F, et al. (2013) A largely random AAV integration profile after LPLD gene therapy. Nat Med 19: 889–891. doi: 10.1038/nm.3230 23770691

39. Schnepp BC, Clark KR, Klemanski DL, Pacak CA, Johnson PR (2003) Genetic fate of recombinant adeno-associated virus vector genomes in muscle. J Virol 77: 3495–3504. 12610125

40. Li H, Malani N, Hamilton SR, Schlachterman A, Bussadori G, et al. (2011) Assessing the potential for AAV vector genotoxicity in a murine model. Blood 117: 3311–3319. doi: 10.1182/blood-2010-08-302729 21106988

41. Wilson NA, Reed J, Napoe GS, Piaskowski S, Szymanski A, et al. (2006) Vaccine-induced cellular immune responses reduce plasma viral concentrations after repeated low-dose challenge with pathogenic simian immunodeficiency virus SIVmac239. J Virol 80: 5875–5885. 16731926

42. Martins MA, Wilson NA, Piaskowski SM, Weisgrau KL, Furlott JR, et al. (2014) Vaccination with Gag, Vif, and Nef gene fragments affords partial control of viral replication after mucosal challenge with SIVmac239. J Virol 88: 7493–7516. doi: 10.1128/JVI.00601-14 24741098

43. Hansen SG, Ford JC, Lewis MS, Ventura AB, Hughes CM, et al. (2011) Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature 473: 523–527. doi: 10.1038/nature10003 21562493

44. Letvin NL, Rao SS, Montefiori DC, Seaman MS, Sun Y, et al. (2011) Immune and Genetic Correlates of Vaccine Protection Against Mucosal Infection by SIV in Monkeys. Sci Transl Med 3: 81ra36. doi: 10.1126/scitranslmed.3002351 21543722

45. Roederer M, Keele BF, Schmidt SD, Mason RD, Welles HC, et al. (2014) Immunological and virological mechanisms of vaccine-mediated protection against SIV and HIV. Nature 505: 502–508. doi: 10.1038/nature12893 24352234

46. Burton DR, Hessell AJ, Keele BF, Klasse PJ, Ketas TA, et al. (2011) Limited or no protection by weakly or nonneutralizing antibodies against vaginal SHIV challenge of macaques compared with a strongly neutralizing antibody. Proc Natl Acad Sci U S A 108: 11181–11186. doi: 10.1073/pnas.1103012108 21690411

47. Moog C, Dereuddre-Bosquet N, Teillaud JL, Biedma ME, Holl V, et al. (2014) Protective effect of vaginal application of neutralizing and nonneutralizing inhibitory antibodies against vaginal SHIV challenge in macaques. Mucosal Immunol 7: 46–56. doi: 10.1038/mi.2013.23 23591718

48. Moldt B, Schultz N, Dunlop DC, Alpert MD, Harvey JD, et al. (2011) A panel of IgG1 b12 variants with selectively diminished or enhanced affinity for Fcgamma receptors to define the role of effector functions in protection against HIV. J Virol 85: 10572–10581. doi: 10.1128/JVI.05541-11 21849450

49. Moldt B, Shibata-Koyama M, Rakasz EG, Schultz N, Kanda Y, et al. (2012) A nonfucosylated variant of the anti-HIV-1 monoclonal antibody b12 has enhanced FcgammaRIIIa-mediated antiviral activity in vitro but does not improve protection against mucosal SHIV challenge in macaques. J Virol 86: 6189–6196. doi: 10.1128/JVI.00491-12 22457527

50. Hessell AJ, Hangartner L, Hunter M, Havenith CE, Beurskens FJ, et al. (2007) Fc receptor but not complement binding is important in antibody protection against HIV. Nature 449: 101–104. 17805298

51. Hessell AJ, Poignard P, Hunter M, Hangartner L, Tehrani DM, et al. (2009) Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques. Nat Med 15: 951–954. doi: 10.1038/nm.1974 19525965

52. Bournazos S, Klein F, Pietzsch J, Seaman MS, Nussenzweig MC, et al. (2014) Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity. Cell 158: 1243–1253. doi: 10.1016/j.cell.2014.08.023 25215485

53. Alpert MD, Harvey JD, Lauer WA, Reeves RK, Piatak M Jr., et al. (2012) ADCC develops over time during persistent infection with live-attenuated SIV and is associated with complete protection against SIV(mac)251 challenge. PLoS Pathog 8: e1002890. doi: 10.1371/journal.ppat.1002890 22927823

54. Bonsignori M, Pollara J, Moody MA, Alpert MD, Chen X, et al. (2012) Antibody-dependent cellular cytotoxicity-mediating antibodies from an HIV-1 vaccine efficacy trial target multiple epitopes and preferentially use the VH1 gene family. J Virol 86: 11521–11532. doi: 10.1128/JVI.01023-12 22896626

55. Lewis GK (2014) Role of Fc-mediated antibody function in protective immunity against HIV-1. Immunology 142: 46–57. 24843871

56. Florese RH, Demberg T, Xiao P, Kuller L, Larsen K, et al. (2009) Contribution of nonneutralizing vaccine-elicited antibody activities to improved protective efficacy in rhesus macaques immunized with Tat/Env compared with multigenic vaccines. J Immunol 182: 3718–3727. doi: 10.4049/jimmunol.0803115 19265150

57. Gomez-Roman VR, Patterson LJ, Venzon D, Liewehr D, Aldrich K, et al. (2005) Vaccine-elicited antibodies mediate antibody-dependent cellular cytotoxicity correlated with significantly reduced acute viremia in rhesus macaques challenged with SIVmac251. J Immunol 174: 2185–2189. 15699150

58. Ackerman ME, Crispin M, Yu X, Baruah K, Boesch AW, et al. (2013) Natural variation in Fc glycosylation of HIV-specific antibodies impacts antiviral activity. J Clin Invest 123: 2183–2192. doi: 10.1172/JCI65708 23563315

59. Ackerman ME, Dugast AS, Alter G (2012) Emerging concepts on the role of innate immunity in the prevention and control of HIV infection. Annu Rev Med 63: 113–130. doi: 10.1146/annurev-med-050310-085221 22077718

60. Forthal D, Hope TJ, Alter G (2013) New paradigms for functional HIV-specific nonneutralizing antibodies. Curr Opin HIV AIDS 8: 393–401. doi: 10.1097/COH.0b013e328363d486 23924999

61. Ferrara C, Grau S, Jager C, Sondermann P, Brunker P, et al. (2011) Unique carbohydrate-carbohydrate interactions are required for high affinity binding between FcgammaRIII and antibodies lacking core fucose. Proc Natl Acad Sci U S A 108: 12669–12674. doi: 10.1073/pnas.1108455108 21768335

62. Scallon BJ, Tam SH, McCarthy SG, Cai AN, Raju TS (2007) Higher levels of sialylated Fc glycans in immunoglobulin G molecules can adversely impact functionality. Mol Immunol 44: 1524–1534. 17045339

63. Trkola A, Kuster H, Rusert P, Joos B, Fischer M, et al. (2005) Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive transfer of human neutralizing antibodies. Nat Med 11: 615–622. 15880120

64. Joos B, Trkola A, Kuster H, Aceto L, Fischer M, et al. (2006) Long-term multiple-dose pharmacokinetics of human monoclonal antibodies (MAbs) against human immunodeficiency virus type 1 envelope gp120 (MAb 2G12) and gp41 (MAbs 4E10 and 2F5). Antimicrob Agents Chemother 50: 1773–1779. 16641449

65. Mueller C, Ratner D, Zhong L, Esteves-Sena M, Gao G (2012) Production and discovery of novel recombinant adeno-associated viral vectors. Curr Protoc Microbiol Chapter 14: Unit14D 11.

66. Cline AN, Bess JW, Piatak M Jr., Lifson JD (2005) Highly sensitive SIV plasma viral load assay: practical considerations, realistic performance expectations, and application to reverse engineering of vaccines for AIDS. J Med Primatol 34: 303–312. 16128925