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Cytokine genetic adjuvant facilitates prophylactic intravascular DNA vaccine against acute and latent herpes simplex virus infection in mice

Gene Therapy volume 12, pages 160–168 (2005)Cite this article

Abstract

Intravascular plasmid DNA (pDNA) vaccine encoding herpes simplex virus type 1 (HSV-1) glycoprotein B (gB) effectively induces prophylactic immunity against lethal HSV-1 infection in mice. We investigated whether the vaccine potency is further improved by coadministration of cytokine genes together with a low dose of genetic vaccine. pDNA encoding IL-12, IL-15, IL-18 or IL-21 was capable of elevating survival rates of HSV-1-infected mice when coinjected with 1 μg of gB pDNA, while IL-10 gene delivery failed to affect the effectiveness of the genetic immunization. Although only 17% of mice survived acute HSV infection after the gB pDNA vaccination at a dose of 1 μg, all mice coadministered with 1 μg each of gB and IL-12 pDNAs not only survived the acute infection but also escaped latent infection. In these animals, the neutralizing antibody against HSV-1 was abundantly produced, and CTL activity against the gB antigen was augmented. Coadministration of the gB and IL-12 genes also elevated the serum level of interferon-γ. Adaptive transfer experiments indicated that soluble factors contributed to preventive immunity, while cell components alone were not capable of protecting mice from fatal viral infection. These results strongly suggest potential usefulness of Th1 cytokine genes as effective molecular adjuvants that facilitate specific humoral as well as cellular immune responses elicited by intravascular molecular vaccination.

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References

  1. Manickan E et al. Genetic immunization against herpes simplex virus. Protection is mediated by CD4+ T lymphocytes. J Immunol 1995; 155: 259–265.

    CAS  PubMed  Google Scholar 

  2. McClements WL, Armstrong ME, Keys RD, Liu MA . Immunization with DNA vaccines encoding glycoprotein D or glycoprotein B, alone or in combination, induces protective immunity in animal models of herpes simplex virus-2 disease. Proc Natl Acad Sci USA 1996; 93: 11414–11420.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kuklin N et al. Induction of mucosal immunity against herpes simplex virus by plasmid DNA immunization. J Virol 1997; 71: 3138–3145.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Caselli E et al. Mice genetic immunization with plasmid DNA encoding a secreted form of HSV-1 gB induces a protective immune response against herpes simplex virus type 1 infection. Intervirology 2001; 44: 1–7.

    Article  CAS  PubMed  Google Scholar 

  5. Baghian A et al. Protective immunity against lethal HSV-1 challenge in mice by nucleic acid-based immunisation with herpes simplex virus type-1 genes specifying glycoproteins gB and gD. J Med Microbiol 2002; 5: 350–357.

    Article  Google Scholar 

  6. Kriesel JD, Spruance SL, Daynes RA, Araneo BA . Nucleic acid vaccine encoding gD2 protects mice from herpes simplex virus type 2 disease. J Infect Dis 1996; 173: 536–541.

    Article  CAS  PubMed  Google Scholar 

  7. Nass PH, Elkins KL, Weir JP . Antibody response and protective capacity of plasmid vaccines expressing three different herpes simplex virus glycoproteins. J Infect Dis 1998; 178: 611–617.

    Article  CAS  PubMed  Google Scholar 

  8. Nass PH, Elkins KL, Weir JP . Protective immunity against herpes simplex virus generated by DNA vaccination compared to natural infection. Vaccine 2001; 19: 1538–1546.

    Article  CAS  PubMed  Google Scholar 

  9. Lee S et al. Influence of DNA encoding cytokines on systemic and mucosal immunity following genetic vaccination against herpes simplex virus. Microbes Infect 2003; 5: 571–578.

    Article  CAS  PubMed  Google Scholar 

  10. Liu F, Song YK, Liu D . Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene Therapy 1999; 6: 1258–1266.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang G, Budker V, Wolff JA . High levels of foreign gene expression in hepatocytes after tail vein injections of naked plasmid DNA. Hum Gene Ther 1999; 10: 1735–1737.

    Article  CAS  PubMed  Google Scholar 

  12. Cui FD et al. Highly efficient gene transfer into murine liver achieved by intravenous administration of naked Epstein–Barr virus (EBV)-based plasmid vectors. Gene Therapy 2001; 8: 1508–1513.

    Article  CAS  PubMed  Google Scholar 

  13. Cui FD et al. Intravascular naked DNA vaccine encoding glycoprotein B induces protective humoral and cellular immunity against herpes simplex virus type 1 infection in mice. Gene Therapy 2003; 10: 2059–2066.

    Article  CAS  PubMed  Google Scholar 

  14. Chow YH et al. Development of Th1 and Th2 populations and the nature of immune responses to hepatitis B virus DNA vaccines can be modulated by codelivery of various cytokine genes. J Immunol 1998; 160: 1320–1329.

    CAS  PubMed  Google Scholar 

  15. Kim JJ et al. In vivo engineering of a cellular immune response by coadministration of IL-12 expression vector with a DNA immunogen. J Immunol 1997; 158: 816–826.

    CAS  PubMed  Google Scholar 

  16. Kim JJ et al. Modulation of amplitude and direction of in vivo immune responses by co-administration of cytokine gene expression cassettes with DNA immunogens. Eur J Immunol 1998; 28: 1089–1103.

    Article  CAS  PubMed  Google Scholar 

  17. Kim JJ et al. Cytokine molecular adjuvants modulate immune responses induced by DNA vaccine constructs for HIV-1 and SIV. J Interferon Cytokine Res 1999; 19: 77–84.

    Article  CAS  PubMed  Google Scholar 

  18. Sin JI et al. IL-12 gene as a DNA vaccine adjuvant in a herpes mouse model: IL-12 enhances Th1-type CD4+ T cell-mediated protective immunity against herpes simplex virus-2 challenge. J Immunol 1999; 162: 2912–2921.

    CAS  PubMed  Google Scholar 

  19. Moore AC, Kong WP, Chakrabarti BK, Nabel GJ . Effects of antigen and genetic adjuvants on immune responses to human immunodeficiency virus DNA vaccines in mice. J Virol 2002; 76: 243–250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Martin E, Kamath AT, Briscoe H, Britton WJ . The combination of plasmid interleukin-12 with a single DNA vaccine is more effective than Mycobacterium bovis (baccillus Calmette-Guèrin) in protecting against systemic Mycobacterium avium infection. Immunology 2003; 109: 308–314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Xin KQ et al. IL-15 expression plasmid enhances cell-mediated immunity induced by an HIV-1 DNA vaccine. Vaccine 1999; 17: 858–866.

    Article  CAS  PubMed  Google Scholar 

  22. Zhu M et al. Enhancement of DNA vaccine potency against herpes simplex virus 1 by co-administration of an interleukin-18 expression plasmid as a genetic adjuvant. J Med Microbiol 2003; 52: 223–228.

    Article  PubMed  Google Scholar 

  23. Matsuo R et al. Interleukin-12 protects thermally injured mice from herpes simplex virus type 1 infection. J Leukoc Biol 1996; 59: 623–630.

    Article  CAS  PubMed  Google Scholar 

  24. Kobayashi H et al. Therapeutic protective effects of IL-12 combined with soluble IL-4 receptor against established infections of herpes simplex virus type 1 in thermally injured mice. J Immunol 1999; 162: 7148–7154.

    CAS  PubMed  Google Scholar 

  25. Al-Khatib K, Campbell IL, Carr DJ . Resistance to ocular herpes simplex virus type 1 infection in IL-12 transgenic mice. J Neuroimmunol 2002; 13: 41–48.

    Article  Google Scholar 

  26. Harandi AM, Svennerholm B, Holmgren J, Eriksson K . Interleukin-12 (IL-12) and IL-18 are important in innate defense against genital herpes simplex virus type 2 infection in mice but are not required for the development of acquired gamma interferon-mediated protective immunity. J Virol 2001; 75: 6705–6709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Johnson RM, Lancki DW, Fitch FW, Spear PG . Herpes simplex virus glycoprotein D is recognized as antigen by CD4+ and CD8+ T lymphocytes from infected mice. Characterization of T cell clones. J Immuol 1990; 145: 702–710.

    CAS  Google Scholar 

  28. Koelle DM et al. Antigenic specificities of human CD4+ T-cell clones recovered from recurrent genital herpes simplex virus type 2 lesions. J Virol 1994; 68: 2803–2810.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Nugent CT, Wolcott RM, Chervenak R, Jennings SR . Analysis of cytolytic T-lymphocyte response to herpes simplex virus type 1 glycoprotein B during primary and secondary infection. J Virol 1994; 68: 7644–7648.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Cose SC, Kelly JM, Carbone FR . Characterization of a diverse primary herpes simplex virus type 1 gB-specific cytotoxic T-cell response showing a preferential Vβ bias. J Virol 1995; 69: 5849–5852.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Ghiasi H et al. The importance of MHC-I and II responses in vaccine efficacy against lethal herpes simplex virus type 1 challenge. Immunology 1997; 91: 430–435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bernstein DI, Stanberry LR . Herpes simplex virus vaccines. Vaccine 1999; 17: 1681–1689.

    Article  CAS  PubMed  Google Scholar 

  33. Biron CA et al. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 1999; 17: 189–220.

    Article  CAS  PubMed  Google Scholar 

  34. Niwa H, Yamamura K, Miyazaki J . Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 1991; 108: 193–199.

    Article  CAS  PubMed  Google Scholar 

  35. Yates JL, Warren N, Sugden B . Stable replication of plasmids derived from Epstein–Barr virus in various mammalian cells. Nature 1985; 313: 812–815.

    Article  CAS  PubMed  Google Scholar 

  36. Kishida T et al. Interleukin (IL)-21 and IL-15 genetic transfer synergistically augments therapeutic antitumor immunity and promotes regression of metastatic lymphoma. Mol Ther 2003; 8: 552–558.

    Article  CAS  PubMed  Google Scholar 

  37. Kishida T et al. In vivo electroporation-mediated transfer of interleukin-12 and interleukin-18 genes induces significant antitumor effects against melanoma in mice. Gene Therapy 2001; 8: 1234–1240.

    Article  CAS  PubMed  Google Scholar 

  38. Asada H et al. Significant antitumor effects obtained by autologous tumor cell vaccine engineered to secrete interleukin (IL)-12 and IL-18 by means of the EBV/lipoplex. Mol Ther 2002; 5: 609–616.

    Article  CAS  PubMed  Google Scholar 

  39. Nakanishi H et al. Nonviral genetic transfer of Fas ligand induced significant growth suppression and apoptotic tumor cell death in prostate cancer in vivo. Gene Therapy 2003; 10: 434–442.

    Article  CAS  PubMed  Google Scholar 

  40. Kishida T et al. Electrochemo-gene-therapy of cancer: intratumoral delivery of interleukin-12 gene and bleomycin synergistically induced therapeutic immunity and suppressed subcutaneous and metastatic melanomas in mice. Mol Ther 2003; 8: 738–745.

    Article  CAS  PubMed  Google Scholar 

  41. Itokawa Y et al. IL-12 genetic administration suppressed metastatic liver tumor unsusceptible to CTL. Biochem Biophys Res Commun 2004; 314: 1072–1079.

    Article  CAS  PubMed  Google Scholar 

  42. Kita M, Tong LJ, Imanishi J . Induction de I′ARN messager des cytokines par I′infection de I′herpes simplex virus chez la souris. C R Soc Biol 1993; 187: 561–568.

    CAS  Google Scholar 

  43. Con RW et al. Extended duration of herpes simplex virus DNA in genital lesions detected by the polymerase chain reaction. J Infect Dis 1991; 164: 757–760.

    Article  Google Scholar 

Download references

Acknowledgements

The present study was supported by a grant in aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology. The bicistronic mIL-12 gene expression cassette and mouse IL-18 cDNA were generous gifts from Dr H Tahara (the Institute of Medical Science, University of Tokyo, Tokyo, Japan), and mouse IL-10 cDNA was kindly provided by Dr KW Moore (DNAX Research Institute, CA, USA). We also thank Dr WTV Germeraad (Academic Hospital Maastricht, Maastricht, the Netherlands) for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Microbiology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    F-D Cui, H Asada, T Kishida, M Shin-Ya, T Nakaya, M Kita, J Imanishi & O Mazda

  2. Department of Microbiology and Immunology, Yanbian University College of Medicine, Yanji, China

    F-D Cui

  3. Department of Internal Medicine, Affiliated Hospital of Yanbian University College of Medicine, Yanji, China

    M-L Jin

  4. Division of Gastroenterology and Hepatology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan

    M Ishii, M Iwai & T Okanoue

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  1. F-D Cui
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Cui, FD., Asada, H., Jin, ML. et al. Cytokine genetic adjuvant facilitates prophylactic intravascular DNA vaccine against acute and latent herpes simplex virus infection in mice. Gene Ther 12, 160–168 (2005). https://doi.org/10.1038/sj.gt.3302393

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