Persistence of Integrase-Deficient Lentiviral Vectors Correlates with the Induction of STING-Independent CD8 T Cell Responses

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2019 Jan 31

PMID 30699352

Citations 18

Authors

Celine Cousin

Marine Oberkampf

Tristan Felix

Pierre Rosenbaum

Robert Weil

Sylvie Fabrega

Valeria Morante

Donatella Negri

Andrea Cara

Gilles Dadaglio

Claude Leclerc

Affiliations

Soon will be listed here.

Abstract

Lentiviruses are among the most promising viral vectors for in vivo gene delivery. To overcome the risk of insertional mutagenesis, integrase-deficient lentiviral vectors (IDLVs) have been developed. We show here that strong and persistent specific cytotoxic T cell (CTL) responses are induced by IDLVs, which persist several months after a single injection. These responses were associated with the induction of mild and transient maturation of dendritic cells (DCs) and with the production of low levels of inflammatory cytokines and chemokines. They were independent of the IFN-I, TLR/MyD88, interferon regulatory factor (IRF), retinoic acid induced gene I (RIG-I), and stimulator of interferon genes (STING) pathways but require NF-κB signaling in CD11c DCs. Despite the lack of integration of IDLVs, the transgene persists for 3 months in the spleen and liver of IDLV-injected mice. These results demonstrate that the capacity of IDLVs to trigger persistent adaptive responses is mediated by a weak and transient innate response, along with the persistence of the vector in tissues.

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References

Karwacz K, Mukherjee S, Apolonia L, Blundell M, Bouma G, Escors D . Nonintegrating lentivector vaccines stimulate prolonged T-cell and antibody responses and are effective in tumor therapy. J Virol. 2009; 83(7):3094-103. PMC: 2655594. DOI: 10.1128/JVI.02519-08. View

Probst H, Lagnel J, Kollias G, van den Broek M . Inducible transgenic mice reveal resting dendritic cells as potent inducers of CD8+ T cell tolerance. Immunity. 2003; 18(5):713-20. DOI: 10.1016/s1074-7613(03)00120-1. View

Pichlmair A, Diebold S, Gschmeissner S, Takeuchi Y, Ikeda Y, Collins M . Tubulovesicular structures within vesicular stomatitis virus G protein-pseudotyped lentiviral vector preparations carry DNA and stimulate antiviral responses via Toll-like receptor 9. J Virol. 2006; 81(2):539-47. PMC: 1797478. DOI: 10.1128/JVI.01818-06. View

Swiecki M, Gilfillan S, Vermi W, Wang Y, Colonna M . Plasmacytoid dendritic cell ablation impacts early interferon responses and antiviral NK and CD8(+) T cell accrual. Immunity. 2010; 33(6):955-66. PMC: 3588567. DOI: 10.1016/j.immuni.2010.11.020. View

Apostolopoulos V, McKenzie I, Lees C, Matthaei K, Young I . A role for IL-5 in the induction of cytotoxic T lymphocytes in vivo. Eur J Immunol. 2000; 30(6):1733-9. DOI: 10.1002/1521-4141(200006)30:6<1733::AID-IMMU1733>3.0.CO;2-E. View

Beignon A, Mollier K, Liard C, Coutant F, Munier S, Riviere J . Lentiviral vector-based prime/boost vaccination against AIDS: pilot study shows protection against Simian immunodeficiency virus SIVmac251 challenge in macaques. J Virol. 2009; 83(21):10963-74. PMC: 2772810. DOI: 10.1128/JVI.01284-09. View

Cartier N, Hacein-Bey-Abina S, Bartholomae C, Veres G, Schmidt M, Kutschera I . Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science. 2009; 326(5954):818-23. DOI: 10.1126/science.1171242. View

Breckpot K, Escors D, Arce F, Lopes L, Karwacz K, Van Lint S . HIV-1 lentiviral vector immunogenicity is mediated by Toll-like receptor 3 (TLR3) and TLR7. J Virol. 2010; 84(11):5627-36. PMC: 2876620. DOI: 10.1128/JVI.00014-10. View

Gil J, Alcami J, Esteban M . Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complex. Oncogene. 2000; 19(11):1369-78. DOI: 10.1038/sj.onc.1203448. View

10.

Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K . Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol. 2002; 3(2):196-200. DOI: 10.1038/ni758. View

11.

Negri D, Michelini Z, Baroncelli S, Spada M, Vendetti S, Buffa V . Successful immunization with a single injection of non-integrating lentiviral vector. Mol Ther. 2007; 15(9):1716-23. DOI: 10.1038/sj.mt.6300241. View

12.

Hervas-Stubbs S, Olivier A, Boisgerault F, Thieblemont N, Leclerc C . TLR3 ligand stimulates fully functional memory CD8+ T cells in the absence of CD4+ T-cell help. Blood. 2007; 109(12):5318-26. DOI: 10.1182/blood-2006-10-053256. View

13.

Hervas-Stubbs S, Riezu-Boj J, Mancheno U, Rueda P, Lopez L, Alignani D . Conventional but not plasmacytoid dendritic cells foster the systemic virus-induced type I IFN response needed for efficient CD8 T cell priming. J Immunol. 2014; 193(3):1151-61. PMC: 4105236. DOI: 10.4049/jimmunol.1301440. View

14.

Rossetti M, Gregori S, Hauben E, Brown B, Sergi Sergi L, Naldini L . HIV-1-derived lentiviral vectors directly activate plasmacytoid dendritic cells, which in turn induce the maturation of myeloid dendritic cells. Hum Gene Ther. 2010; 22(2):177-88. DOI: 10.1089/hum.2010.085. View

15.

Israel A . The IKK complex, a central regulator of NF-kappaB activation. Cold Spring Harb Perspect Biol. 2010; 2(3):a000158. PMC: 2829958. DOI: 10.1101/cshperspect.a000158. View

16.

Sakuma T, Barry M, Ikeda Y . Lentiviral vectors: basic to translational. Biochem J. 2012; 443(3):603-18. DOI: 10.1042/BJ20120146. View

17.

Jung S, Unutmaz D, Wong P, Sano G, de Los Santos K, Sparwasser T . In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. Immunity. 2002; 17(2):211-20. PMC: 3689299. DOI: 10.1016/s1074-7613(02)00365-5. View

18.

Cox M, Kahan S, Zajac A . Anti-viral CD8 T cells and the cytokines that they love. Virology. 2012; 435(1):157-69. PMC: 3580945. DOI: 10.1016/j.virol.2012.09.012. View

19.

Beignon A, McKenna K, Skoberne M, Manches O, DaSilva I, Kavanagh D . Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions. J Clin Invest. 2005; 115(11):3265-75. PMC: 1253628. DOI: 10.1172/JCI26032. View

20.

Wherry E, Ahmed R . Memory CD8 T-cell differentiation during viral infection. J Virol. 2004; 78(11):5535-45. PMC: 415833. DOI: 10.1128/JVI.78.11.5535-5545.2004. View