1887

Abstract

Currently, many DNA vaccines against infectious diseases are in clinical trials; however, their efficacy needs to be improved. The potency of DNA immunogen can be optimized by targeting technologies. In the current study, to increase the efficacy of NS1 encoded by plasmid, proteasome targeting was applied. NS1 variants with or without translocation sequence and with ornithine decarboxylase as a signal of proteasomal degradation were tested for expression, localization, protein turnover, proteasomal degradation and protection properties. Deletion of translocation signal abrogated presentation of NS1 on the cell surface and increased proteasomal processing of NS1. Fusion with ornithine decarboxylase led to an increase of protein turnover and the proteasome degradation rate of NS1. Immunization with NS1 variants with increased proteasome processing protected mice from viral challenge only partially; however, the survival time of infected mice was prolonged in these groups. These data can give a presupposition for formulation of specific immune therapy for infected individuals.

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2017-02-20
2019-09-18
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References

  1. Ishikawa T, Yamanaka A, Konishi E. A review of successful flavivirus vaccines and the problems with those flaviviruses for which vaccines are not yet available. Vaccine 2014;32:1326–1337 [CrossRef][PubMed]
    [Google Scholar]
  2. Rastogi M, Sharma N, Singh SK. Flavivirus NS1: a multifaceted enigmatic viral protein. Virol J 2016;13:131 [CrossRef][PubMed]
    [Google Scholar]
  3. Muller DA, Young PR. The flavivirus NS1 protein: molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker. Antiviral Res 2013;98:192–208 [CrossRef][PubMed]
    [Google Scholar]
  4. Costa SM, Azevedo AS, Paes MV, Sarges FS, Freire MS et al. DNA vaccines against dengue virus based on the ns1 gene: the influence of different signal sequences on the protein expression and its correlation to the immune response elicited in mice. Virology 2007;358:413–423 [CrossRef][PubMed]
    [Google Scholar]
  5. Lin YL, Chen LK, Liao CL, Yeh CT, Ma SH et al. DNA immunization with Japanese encephalitis virus nonstructural protein NS1 elicits protective immunity in mice. J Virol 1998;72:191–200[PubMed]
    [Google Scholar]
  6. Wu SF, Liao CL, Lin YL, Yeh CT, Chen LK et al. Evaluation of protective efficacy and immune mechanisms of using a non-structural protein NS1 in DNA vaccine against dengue 2 virus in mice. Vaccine 2003;21:3919–3929[PubMed][CrossRef]
    [Google Scholar]
  7. Timofeev AV, Butenko VM, Stephenson JR. Genetic vaccination of mice with plasmids encoding the NS1 non-structural protein from tick-borne encephalitis virus and dengue 2 virus. Virus Genes 2004;28:85–97 [CrossRef][PubMed]
    [Google Scholar]
  8. Jacobs SC, Stephenson JR, Wilkinson GW. High-level expression of the tick-borne encephalitis virus NS1 protein by using an adenovirus-based vector: protection elicited in a murine model. J Virol 1992;66:2086–2095[PubMed]
    [Google Scholar]
  9. Falgout B, Chanock R, Lai CJ. Proper processing of dengue virus nonstructural glycoprotein NS1 requires the N-terminal hydrophobic signal sequence and the downstream nonstructural protein NS2a. J Virol 1989;63:1852–1860[PubMed]
    [Google Scholar]
  10. Fan WF, Mason PW. Membrane association and secretion of the Japanese encephalitis virus NS1 protein from cells expressing NS1 cDNA. Virology 1990;177:470–476[PubMed][CrossRef]
    [Google Scholar]
  11. Gritsun TS, Liapustin VN, Shatalov AG, Lashkevich VA. [Multiple forms of the NS1 protein as the main component of the nonvirion ("soluble") antigen of the tick-borne encephalitis virus]. Vopr Virusol 1990;35:471–474 (in Russian)[PubMed]
    [Google Scholar]
  12. Le Moine A, Surquin M, Demoor FX, Noël JC, Nahori MA et al. IL-5 mediates eosinophilic rejection of MHC class II-disparate skin allografts in mice. J Immunol 1999;163:3778–3784[PubMed]
    [Google Scholar]
  13. Crooks AJ, Lee JM, Easterbrook LM, Timofeev AV, Stephenson JR. The NS1 protein of tick-borne encephalitis virus forms multimeric species upon secretion from the host cell. J Gen Virol 1994;75:3453–3460 [CrossRef][PubMed]
    [Google Scholar]
  14. Timofeev AV, Ozherelkov SV, Pronin AV, Deeva AV, Karganova GG et al. Immunological basis for protection in a murine model of tick-borne encephalitis by a recombinant adenovirus carrying the gene encoding the NS1 non-structural protein. J Gen Virol 1998;79:689–695 [CrossRef][PubMed]
    [Google Scholar]
  15. Falconar AK. The dengue virus nonstructural-1 protein (NS1) generates antibodies to common epitopes on human blood clotting, integrin/adhesin proteins and binds to human endothelial cells: potential implications in haemorrhagic fever pathogenesis. Arch Virol 1997;142:897–916[PubMed][CrossRef]
    [Google Scholar]
  16. Cheng HJ, Lin CF, Lei HY, Liu HS, Yeh TM et al. Proteomic analysis of endothelial cell autoantigens recognized by anti-dengue virus nonstructural protein 1 antibodies. Exp Biol Med 2009;234:63–73 [CrossRef][PubMed]
    [Google Scholar]
  17. Avirutnan P, Fuchs A, Hauhart RE, Somnuke P, Youn S et al. Antagonism of the complement component C4 by flavivirus nonstructural protein NS1. J Exp Med 2010;207:793–806 [CrossRef][PubMed]
    [Google Scholar]
  18. Li L, Petrovsky N. Molecular mechanisms for enhanced DNA vaccine immunogenicity. Expert Rev Vaccines 2016;15:313–329 [CrossRef][PubMed]
    [Google Scholar]
  19. Li L, Saade F, Petrovsky N. The future of human DNA vaccines. J Biotechnol 2012;162:171–182 [CrossRef][PubMed]
    [Google Scholar]
  20. Leifert JA, Rodriguez-Carreno MP, Rodriguez F, Whitton JL. Targeting plasmid-encoded proteins to the antigen presentation pathways. Immunol Rev 2004;199:40–53 [CrossRef][PubMed]
    [Google Scholar]
  21. Blum JS, Wearsch PA, Cresswell P. Pathways of antigen processing. Annu Rev Immunol 2013;31:443–473 [CrossRef][PubMed]
    [Google Scholar]
  22. Starodubova ES, Isaguliants MG, Karpov VL. Regulation of immunogen processing: signal sequences and their application for the new generation of DNA-vaccines. Acta Naturae 2010;2:53–60[PubMed]
    [Google Scholar]
  23. Tobery T, Siliciano RF. Cutting edge: induction of enhanced CTL-dependent protective immunity in vivo by N-end rule targeting of a model tumor antigen. J Immunol 1999;162:639–642[PubMed]
    [Google Scholar]
  24. Ilyinskii PO, Meriin AB, Gabai VL, Zhirnov OP, Thoidis G et al. Prime-boost vaccination with a combination of proteosome-degradable and wild-type forms of two influenza proteins leads to augmented CTL response. Vaccine 2008;26:2177–2185 [CrossRef][PubMed]
    [Google Scholar]
  25. Starodubova ES, Isaguliants MG, Karpov VL. [Artifitial increase of HIV-1 reverse transcriptase turnover through proteasome pathway]. Mol Biol 2006;40:982–988 (in Russian)[PubMed][CrossRef]
    [Google Scholar]
  26. Starodubova ES, Boberg A, Litvina M, Morozov A, Petrakova NV et al. HIV-1 reverse transcriptase artificially targeted for proteasomal degradation induces a mixed Th1/Th2-type immune response. Vaccine 2008;26:5170–5176 [CrossRef][PubMed]
    [Google Scholar]
  27. Starodubova E, Boberg A, Kashuba EV, Wahren B, Karpov V et al. HIV-1 reverse transcriptase targeted for proteasomal degradation as a prototype vaccine against drug-resistant HIV-1. Vaccine 2006;24:4541–4547 [CrossRef][PubMed]
    [Google Scholar]
  28. Peng S, Ji H, Trimble C, He L, Tsai YC et al. Development of a DNA vaccine targeting human papillomavirus type 16 oncoprotein E6. J Virol 2004;78:8468–8476 [CrossRef][PubMed]
    [Google Scholar]
  29. Lindenbach BD, Thiel HJ, Rice CM. Flaviviridae: the viruses and their replication. In Knipe DM, Howley PM. (editors) Fields Virology, 5th ed. Philadelphia: Lippincot-Raven; 2007; pp.931–959
    [Google Scholar]
  30. Aleshin SE, Timofeev AV, Khoretonenko MV, Zakharova LG, Pashvykina GV et al. Combined prime-boost vaccination against tick-borne encephalitis (TBE) using a recombinant vaccinia virus and a bacterial plasmid both expressing TBE virus non-structural NS1 protein. BMC Microbiol 2005;5:45 [CrossRef][PubMed]
    [Google Scholar]
  31. Murakami Y, Matsufuji S, Kameji T, Hayashi S, Igarashi K et al. Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination. Nature 1992;360:597–599 [CrossRef][PubMed]
    [Google Scholar]
  32. Li X, Coffino P. Distinct domains of antizyme required for binding and proteolysis of ornithine decarboxylase. Mol Cell Biol 1994;14:87–92[PubMed][CrossRef]
    [Google Scholar]
  33. Loetscher P, Pratt G, Rechsteiner M. The C terminus of mouse ornithine decarboxylase confers rapid degradation on dihydrofolate reductase. Support for the pest hypothesis. J Biol Chem 1991;266:11213–11220[PubMed]
    [Google Scholar]
  34. Matsuzawa S, Cuddy M, Fukushima T, Reed JC. Method for targeting protein destruction by using a ubiquitin-independent, proteasome-mediated degradation pathway. Proc Natl Acad Sci USA 2005;102:14982–14987 [CrossRef][PubMed]
    [Google Scholar]
  35. Schlesinger JJ, Foltzer M, Chapman S. The FC portion of antibody to yellow fever virus NS1 is a determinant of protection against YF encephalitis in mice. Virology 1993;192:132–141 [CrossRef][PubMed]
    [Google Scholar]
  36. Diamond MS, Pierson TC, Fremont DH. The structural immunology of antibody protection against West Nile virus. Immunol Rev 2008;225:212–225 [CrossRef][PubMed]
    [Google Scholar]
  37. Green S, Rothman A. Immunopathological mechanisms in dengue and dengue hemorrhagic fever. Curr Opin Infect Dis 2006;19:429–436 [CrossRef][PubMed]
    [Google Scholar]
  38. Netland J, Bevan MJ. CD8 and CD4 T cells in West Nile virus immunity and pathogenesis. Viruses 2013;5:2573–2584 [CrossRef][PubMed]
    [Google Scholar]
  39. Rivino L. T cell immunity to dengue virus and implications for vaccine design. Expert Rev Vaccines 2016;15:443–453 [CrossRef][PubMed]
    [Google Scholar]
  40. Vaughan K, Greenbaum J, Blythe M, Peters B, Sette A. Meta-analysis of all immune epitope data in the Flavivirus genus: inventory of current immune epitope data status in the context of virus immunity and immunopathology. Viral Immunol 2010;23:259–284 [CrossRef][PubMed]
    [Google Scholar]
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