Vaccine protection against rectal acquisition of SIVmac239 in rhesus macaques

English version

Autoři: Lucas Gonzalez-Nieto ^aff001; Isabelle M. Castro ^aff001; Georg F. Bischof ^aff001; Young C. Shin ^aff001; Michael J. Ricciardi ^aff001; Varian K. Bailey ^aff001; Christine M. Dang ^aff001; Nuria Pedreño-Lopez ^aff001; Diogo M. Magnani ^aff001; Keisuke Ejima ^aff002; David B. Allison ^aff002; Hwi Min Gil ^aff003; David T. Evans ^aff003; Eva G. Rakasz ^aff003; Jeffrey D. Lifson ^aff005; Ronald C. Desrosiers ^aff001; Mauricio A. Martins ^aff001
Působiště autorů: Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida, United States of America ^aff001; Department of Epidemiology and Biostatistics, Indiana University School of Public Health-Bloomington, Bloomington, Indiana, United States of America ^aff002; Wisconsin National Primate Research Center, University of Wisconsin, Madison, Wisconsin, United States of America ^aff003; Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America ^aff004; AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America ^aff005
Vyšlo v časopise: Vaccine protection against rectal acquisition of SIVmac239 in rhesus macaques. PLoS Pathog 15(9): e32767. doi:10.1371/journal.ppat.1008015
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008015

Souhrn

A prophylactic vaccine against human immunodeficiency virus (HIV) remains a top priority in biomedical research. Given the failure of conventional immunization protocols to confer robust protection against HIV, new and unconventional approaches may be needed to generate protective anti-HIV immunity. Here we vaccinated rhesus macaques (RMs) with a recombinant (r)DNA prime (without any exogenous adjuvant), followed by a booster with rhesus monkey rhadinovirus (RRV)−a herpesvirus that establishes persistent infection in RMs (Group 1). Both the rDNA and rRRV vectors encoded a near-full-length simian immunodeficiency virus (SIVnfl) genome that assembles noninfectious SIV particles and expresses all nine SIV gene products. This rDNA/rRRV-SIVnfl vaccine regimen induced persistent anti-Env antibodies and CD8+ T-cell responses against the entire SIV proteome. Vaccine efficacy was assessed by repeated, marginal-dose, intrarectal challenges with SIVmac239. Encouragingly, vaccinees in Group 1 acquired SIVmac239 infection at a significantly delayed rate compared to unvaccinated controls (Group 3). In an attempt to improve upon this outcome, a separate group of rDNA/rRRV-SIVnfl-vaccinated RMs (Group 2) was treated with a cytotoxic T-lymphocyte antigen-4 (CTLA-4)-blocking monoclonal antibody during the vaccine phase and then challenged in parallel with Groups 1 and 3. Surprisingly, Group 2 was not significantly protected against SIVmac239 infection. In sum, SIVnfl vaccination can protect RMs against rigorous mucosal challenges with SIVmac239, a feat that until now had only been accomplished by live-attenuated strains of SIV. Further work is needed to identify the minimal requirements for this protection and whether SIVnfl vaccine efficacy can be improved by means other than anti-CTLA-4 adjuvant therapy.

Klíčová slova:

Cytotoxic T cells – Enzyme-linked immunoassays – Immune response – Rectum – T cells – Vaccination and immunization – Vaccines – SIV

Zdroje

1. UNAIDS. Fact sheet—World AIDS Day 2018. 2018

2. Medlock J, Pandey A, Parpia AS, Tang A, Skrip LA, Galvani AP. Effectiveness of UNAIDS targets and HIV vaccination across 127 countries. Proc Natl Acad Sci U S A. 2017;114:4017–4022. doi: 10.1073/pnas.1620788114 28320938

3. Buchbinder SP, Mehrotra DV, Duerr A et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet. 2008;372:1881–1893. doi: 10.1016/S0140-6736(08)61591-3 19012954

4. Flynn NM, Forthal DN, Harro CD, Judson FN, Mayer KH, Para MF. Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. J Infect Dis. 2005;191:654–665. doi: 10.1086/428404 15688278

5. Gray GE, Allen M, Moodie Z et al. Safety and efficacy of the HVTN 503/Phambili study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study. Lancet Infect Dis. 2011;11:507–515. doi: 10.1016/S1473-3099(11)70098-6 21570355

6. Hammer SM, Sobieszczyk ME, Janes H et al. Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine. N Engl J Med. 2013;369:2083–2092. doi: 10.1056/NEJMoa1310566 24099601

7. Pitisuttithum P, Gilbert P, Gurwith M et al. Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand. J Infect Dis. 2006;194:1661–1671. doi: 10.1086/508748 17109337

8. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009;361:2209–2220. doi: 10.1056/NEJMoa0908492 19843557

9. Desrosiers RC. Protection against HIV Acquisition in the RV144 Trial. J Virol. 2017;91

10. Gilbert PB, Berger JO, Stablein D et al. Statistical interpretation of the RV144 HIV vaccine efficacy trial in Thailand: a case study for statistical issues in efficacy trials. J Infect Dis. 2011;203:969–975. doi: 10.1093/infdis/jiq152 21402548

11. Shin YC, Bischof GF, Lauer WA et al. A recombinant herpesviral vector containing a near-full-length SIVmac239 genome produces SIV particles and elicits immune responses to all nine SIV gene products. PLoS Pathog. 2018;14:e1007143. doi: 10.1371/journal.ppat.1007143 29912986

12. Wolchok JD, Hodi FS, Weber JS et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci. 2013;1291:1–13. doi: 10.1111/nyas.12180 23772560

13. Walker LSK. EFIS Lecture: Understanding the CTLA-4 checkpoint in the maintenance of immune homeostasis. Immunol Lett. 2017;184:43–50. doi: 10.1016/j.imlet.2017.02.007 28216262

14. Hodi FS, O’Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–723. doi: 10.1056/NEJMoa1003466 20525992

15. Hirao LA, Hokey DA, Morrow MP, Jure-Kunkel MN, Weiner DB. Immune modulation through 4-1BB enhances SIV vaccine protection in non-human primates against SIVmac251 challenge. PLoS One. 2011;6:e24250. doi: 10.1371/journal.pone.0024250 21935390

16. Hokey DA, Yan J, Hirao LA et al. CLTA-4 blockade in vivo promotes the generation of short-lived effector CD8 T cells and a more persistent central memory CD4 T cell response. J Med Primatol. 2008;37 Suppl 2:62–68.

17. Pedicord VA, Montalvo W, Leiner IM, Allison JP. Single dose of anti-CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance. Proc Natl Acad Sci U S A. 2011;108:266–271. doi: 10.1073/pnas.1016791108 21173239

18. Martins MA, Bischof GF, Shin YC et al. Vaccine protection against SIVmac239 acquisition. Proc Natl Acad Sci U S A. 2019;116:1739–1744. doi: 10.1073/pnas.1814584116 30642966

19. Yuste E, Reeves JD, Doms RW, Desrosiers RC. Modulation of Env content in virions of simian immunodeficiency virus: correlation with cell surface expression and virion infectivity. J Virol. 2004;78:6775–6785. doi: 10.1128/JVI.78.13.6775-6785.2004 15194752

20. Mori K, Ringler DJ, Kodama T, Desrosiers RC. Complex determinants of macrophage tropism in env of simian immunodeficiency virus. J Virol. 1992;66:2067–2075. 1548752

21. Swigut T, Alexander L, Morgan J et al. Impact of Nef-mediated downregulation of major histocompatibility complex class I on immune response to simian immunodeficiency virus. J Virol. 2004;78:13335–13344. doi: 10.1128/JVI.78.23.13335-13344.2004 15542684

22. Allen TM, O’Connor DH, Jing P et al. Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature. 2000;407:386–390. doi: 10.1038/35030124 11014195

23. Friedrich TC, Dodds EJ, Yant LJ et al. Reversion of CTL escape-variant immunodeficiency viruses in vivo. Nat Med. 2004;10:275–281. doi: 10.1038/nm998 14966520

24. Rodriguez F, Harkins S, Slifka MK, Whitton JL. Immunodominance in virus-induced CD8(+) T-cell responses is dramatically modified by DNA immunization and is regulated by gamma interferon. J Virol. 2002;76:4251–4259. doi: 10.1128/JVI.76.9.4251-4259.2002 11932390

25. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691–2697. doi: 10.1200/JCO.2012.41.6750 22614989

26. Kvistborg P, Philips D, Kelderman S et al. Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response. Sci Transl Med. 2014;6:254ra128. doi: 10.1126/scitranslmed.3008918 25232180

27. Wei SC, Levine JH, Cogdill AP et al. Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade. Cell. 2017;170:1120–1133.e17. doi: 10.1016/j.cell.2017.07.024 28803728

28. Martins MA, Watkins DI. What Is the Predictive Value of Animal Models for Vaccine Efficacy in Humans? Rigorous Simian Immunodeficiency Virus Vaccine Trials Can Be Instructive. Cold Spring Harb Perspect Biol. 2017

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

30. Evans DT, Bricker JE, Sanford HB et al. 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. 2005;79:7707–7720. doi: 10.1128/JVI.79.12.7707-7720.2005 15919923

31. Iwamoto N, Takahashi N, Seki S et al. Control of Simian Immunodeficiency Virus Replication by Vaccine-Induced Gag- and Vif-Specific CD8+ T Cells. J Virol. 2014;88:425–433. doi: 10.1128/JVI.02634-13 24155398

32. Martins MA, Shin YC, Gonzalez-Nieto L et al. Vaccine-induced immune responses against both Gag and Env improve control of simian immunodeficiency virus replication in rectally challenged rhesus macaques. PLoS Pathog. 2017;13:e1006529. doi: 10.1371/journal.ppat.1006529 28732035

33. Matano T, Kobayashi M, Igarashi H et al. Cytotoxic T lymphocyte-based control of simian immunodeficiency virus replication in a preclinical AIDS vaccine trial. J Exp Med. 2004;199:1709–1718. doi: 10.1084/jem.20040432 15210746

34. Winstone N, Wilson AJ, Morrow G et al. Enhanced control of pathogenic Simian immunodeficiency virus SIVmac239 replication in macaques immunized with an interleukin-12 plasmid and a DNA prime-viral vector boost vaccine regimen. J Virol. 2011;85:9578–9587. doi: 10.1128/JVI.05060-11 21734035

35. Hansen SG, Vieville C, Whizin N et al. Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nat Med. 2009;15:293–299. doi: 10.1038/nm.1935 19219024

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

37. Hansen SG, Piatak MJ, Ventura AB et al. Immune clearance of highly pathogenic SIV infection. Nature. 2013;502:100–104. doi: 10.1038/nature12519 24025770

38. Daniel MD, Kirchhoff F, Czajak SC, Sehgal PK, Desrosiers RC. Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene. Science. 1992;258:1938–1941. doi: 10.1126/science.1470917 1470917

39. Manrique J, Piatak M, Lauer W et al. Influence of mismatch of Env sequences on vaccine protection by live attenuated simian immunodeficiency virus. J Virol. 2013;87:7246–7254. doi: 10.1128/JVI.00798-13 23637396

40. Fukazawa Y, Park H, Cameron MJ et al. Lymph node T cell responses predict the efficacy of live attenuated SIV vaccines. Nat Med. 2012;18:1673–1681. doi: 10.1038/nm.2934 22961108

41. Dintzis HM, Dintzis RZ, Vogelstein B. Molecular determinants of immunogenicity: the immunon model of immune response. Proc Natl Acad Sci U S A. 1976;73:3671–3675. doi: 10.1073/pnas.73.10.3671 62364

42. Aldon Y, McKay PF, Allen J et al. Rational Design of DNA-Expressed Stabilized Native-Like HIV-1 Envelope Trimers. Cell Rep. 2018;24:3324–3338.e5. doi: 10.1016/j.celrep.2018.08.051 30232012

43. Hryniewicz A, Boasso A, Edghill-Smith Y et al. CTLA-4 blockade decreases TGF-beta, IDO, and viral RNA expression in tissues of SIVmac251-infected macaques. Blood. 2006;108:3834–3842. doi: 10.1182/blood-2006-04-010637 16896154

44. Vaccari M, Boasso A, Fenizia C et al. Fatal pancreatitis in simian immunodeficiency virus SIV(mac251)-infected macaques treated with 2’,3’-dideoxyinosine and stavudine following cytotoxic-T-lymphocyte-associated antigen 4 and indoleamine 2,3-dioxygenase blockade. J Virol. 2012;86:108–113. doi: 10.1128/JVI.05609-11 22013040

45. Kverneland AH, Enevold C, Donia M, Bastholt L, Svane IM, Nielsen CH. Development of anti-drug antibodies is associated with shortened survival in patients with metastatic melanoma treated with ipilimumab. Oncoimmunology. 2018;7:e1424674. doi: 10.1080/2162402X.2018.1424674 29721387

46. van Rooij N, van Buuren MM, Philips D et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol. 2013;31:e439–42. doi: 10.1200/JCO.2012.47.7521 24043743

47. Yuan J, Ginsberg B, Page D et al. CTLA-4 blockade increases antigen-specific CD8(+) T cells in prevaccinated patients with melanoma: three cases. Cancer Immunol Immunother. 2011;60:1137–1146. doi: 10.1007/s00262-011-1011-9 21465316

48. Jago CB, Yates J, Câmara NO, Lechler RI, Lombardi G. Differential expression of CTLA-4 among T cell subsets. Clin Exp Immunol. 2004;136:463–471. doi: 10.1111/j.1365-2249.2004.02478.x 15147348

49. Metz DP, Farber DL, Taylor T, Bottomly K. Differential role of CTLA-4 in regulation of resting memory versus naive CD4 T cell activation. J Immunol. 1998;161:5855–5861. 9834064

50. Chambers CA, Sullivan TJ, Truong T, Allison JP. Secondary but not primary T cell responses are enhanced in CTLA-4-deficient CD8+ T cells. Eur J Immunol. 1998;28:3137–3143. doi: 10.1002/(SICI)1521-4141(199810)28:10<3137::AID-IMMU3137>3.0.CO;2-X 9808182

51. Chambers CA, Kuhns MS, Allison JP. Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4(+) T cell responses. Proc Natl Acad Sci U S A. 1999;96:8603–8608. doi: 10.1073/pnas.96.15.8603 10411922

52. Shin YC, Bischof GF, Lauer WA, Desrosiers RC. Importance of codon usage for the temporal regulation of viral gene expression. Proc Natl Acad Sci U S A. 2015;112:14030–14035. doi: 10.1073/pnas.1515387112 26504241

53. Li H, Wang S, Kong R et al. Envelope residue 375 substitutions in simian-human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques. Proc Natl Acad Sci U S A. 2016;113:E3413–22. doi: 10.1073/pnas.1606636113 27247400

54. Montefiori DC. Measuring HIV neutralization in a luciferase reporter gene assay. Methods Mol Biol. 2009;485:395–405. doi: 10.1007/978-1-59745-170-3_26 19020839

55. Alpert MD, Heyer LN, Williams DE et al. 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. 2012;86:12039–12052. doi: 10.1128/JVI.01650-12 22933282

56. Gonzalez-Nieto L, Domingues A, Ricciardi M et al. Analysis of Simian Immunodeficiency Virus-specific CD8+ T-cells in Rhesus Macaques by Peptide-MHC-I Tetramer Staining. J Vis Exp. 2016

57. Saletti G, Çuburu N, Yang JS, Dey A, Czerkinsky C. Enzyme-linked immunospot assays for direct ex vivo measurement of vaccine-induced human humoral immune responses in blood. Nat Protoc. 2013;8:1073–1087. doi: 10.1038/nprot.2013.058 23660756

58. Allison DB, Paultre F, Goran MI, Poehlman ET, Heymsfield SB. Statistical considerations regarding the use of ratios to adjust data. Int J Obes Relat Metab Disord. 1995;19:644–652. 8574275