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Direct application of plasmid DNA containing type I interferon transgenes to vaginal mucosa inhibits HSV-2 mediated mortality

Biological Procedures Online volume 8, pages 55–62 (2006)Cite this article

Abstract

The application of naked DNA containing type I interferon (IFN) transgenes is a promising potential therapeutic approach for controlling chronic viral infections. Herein, we detail the application of this approach that has been extensively used to restrain ocular HSV-1 infection, for antagonizing vaginal HSV-2 infection. We show that application of IFN-α1, -α 5, and -β transgenes to vaginal mouse lumen 24 hours prior to HSV-2 infection reduces HSV-2 mediated mortality by 2.5 to 3-fold. However, other type I IFN transgenes (IFN- α 4, -α 5, -α 6, and -α 9) are non effectual against HSV-2. We further show that the efficacy of IFN-1 transgene treatment is independent of CD4+ T lymphocytes. However, in mice depleted of CD8+ T lymphocytes, the ability of IFN-α 1 transgene treatment to antagonize HSV-2 was lost.

References

  1. Fleming DT, McQuillan GM, Johnson RE, Nahmias AJ, Aral SO, Lee FK, et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med 1997; 337(16):1105–1111.

    Article  PubMed  CAS  Google Scholar 

  2. Sacks SL, Griffiths PD, Corey L, Cohen C, Cunningham A, Dusheiko GM, et al. HSV-2 transmission. Antiviral Res 2004; 63 Suppl 1:S27-S35.

    Article  PubMed  CAS  Google Scholar 

  3. Cherpes TL, Melan MA, Kant JA, Cosentino LA, Meyn LA, Hillier SL. Genital tract shedding of herpes simplex virus type 2 in women: effects of hormonal contraception, bacterial vaginosis, and vaginal group B Streptococcus colonization. Clin Infect Dis 2005; 40(10):1422–1428.

    Article  PubMed  Google Scholar 

  4. Mostad SB, Kreiss JK, Ryncarz AJ, Mandaliya K, Chohan B, Ndinya-Achola J, et al. Cervical shedding of herpes simplex virus in human immunodeficiency virus-infected women: effects of hormonal contraception, pregnancy, and vitamin A deficiency. J Infect Dis 2000; 181(1):58–63.

    Article  PubMed  CAS  Google Scholar 

  5. Wald A. Herpes simplex virus type 2 transmission: risk factors and virus shedding. Herpes 2004; 11 Suppl 3:130A-137A.

    PubMed  Google Scholar 

  6. Celum C, Levine R, Weaver M, Wald A. Genital herpes and human immunodeficiency virus: double trouble. Bull World Health Organ 2004; 82(6):447–453.

    PubMed  Google Scholar 

  7. Wolff MH, Schmitt J, Rahaus M, Dudda H, Hatzmann W. Clinical and subclinical reactivation of genital herpes virus. Intervirology 2002; 45(1):20–23.

    Article  PubMed  Google Scholar 

  8. Raguin G, Malkin JE. Genital herpes: epidemiology and pathophysiology. Update and new perspectives. Ann Med Interne (Paris) 1997; 148(8):530–533.

    CAS  Google Scholar 

  9. Liu V, Bigby M. Reactivation of genital herpes simplex virus 2 infection in asymptomatic seropositive persons is frequent. Arch Dermatol 2000; 136(9):1141–1142.

    Article  PubMed  CAS  Google Scholar 

  10. Tran TH, Stanescu D, Caspers-Velu L, Rozenberg F, Liesnard C, Gaudric A, et al. Clinical characteristics of acute HSV-2 retinal necrosis. Am J Ophthalmol 2004; 137(5):872–879.

    Article  PubMed  Google Scholar 

  11. Inoda S, Wakakura M, Hirata J, Nakazato N, Toyo-Oka Y. Stromal keratitis and anterior uveitis due to herpes simplex virus-2 in a young child. Jpn J Ophthalmol 2001; 45(6):618–621.

    Article  PubMed  CAS  Google Scholar 

  12. Kleinschmidt-DeMasters BK, Gilden DH. The expanding spectrum of herpesvirus infections of the nervous system. Brain Pathol 2001; 11(4):440–451.

    Article  PubMed  CAS  Google Scholar 

  13. Corey L. The current trend in genital herpes. Progress in prevention. Sex Transm Dis 1994; 21(2 Suppl):S38-S44.

    PubMed  CAS  Google Scholar 

  14. Corey L, Langenberg AG, Ashley R, Sekulovich RE, Izu AE, Douglas JM Jr., et al. Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection: two randomized controlled trials. Chiron HSV Vaccine Study Group. Jama 1999; 282(4):331–340.

    Article  PubMed  CAS  Google Scholar 

  15. Rajcani J, Mosko T, Rezuchova I. Current developments in viral DNA vaccines: shall they solve the unsolved? Rev Med Virol 2005; 15(5):303–325.

    Article  PubMed  CAS  Google Scholar 

  16. Rouse BT, Nair S, Rouse RJ, Yu Z, Kuklin N, Karem K, et al. DNA vaccines and immunity to herpes simplex virus. Curr Top Microbiol Immunol 1998; 226:69–78.

    PubMed  CAS  Google Scholar 

  17. Stanberry LR, Cunningham AL, Mindel A, Scott LL, Spruance SL, Aoki FY, et al. Prospects for control of herpes simplex virus disease through immunization. Clin Infect Dis 2000; 30(3):549–566.

    Article  PubMed  CAS  Google Scholar 

  18. McClements WL, Armstrong ME, Keys RD, Liu MA. The prophylactic effect of immunization with DNA encoding herpes simplex virus glycoproteins on HSV-induced disease in guinea pigs. Vaccine 1997; 15(8):857–860.

    Article  PubMed  CAS  Google Scholar 

  19. Lee HH, Cha SC, Jang DJ, Lee JK, Choo DW, Kim YS, et al. Immunization with combined HSV-2 glycoproteins B2: D2 gene DNAs: protection against lethal intravaginal challenges in mice. Virus Genes 2002; 25(2):179–188.

    Article  PubMed  CAS  Google Scholar 

  20. Nass PH, Elkins KL, Weir JP. Protective immunity against herpes simplex virus generated by DNA vaccination compared to natural infection. Vaccine 2001; 19(11–12):1538–1546.

    Article  PubMed  CAS  Google Scholar 

  21. Lee S, Gierynska M, Eo SK, Kuklin N, Rouse BT. Influence of DNA encoding cytokines on systemic and mucosal immunity following genetic vaccination against herpes simplex virus. Microbes Infect 2003; 5(7):571–578.

    Article  PubMed  CAS  Google Scholar 

  22. Emonyi IW, Gray RH, Zenilman J, Schmidt K, Wawer MJ, Sewankambo KN, et al. Sero-prevalence of Herpes simplex virus type 2 (HSV-2) in Rakai district, Uganda. East Afr Med J 2000; 77(8):428–430.

    PubMed  CAS  Google Scholar 

  23. Austin BA, James C, Silverman RH, Carr DJ. Critical role for the oligoadenylate synthetase/RNase L pathway in response to IFN-beta during acute ocular herpes simplex virus type 1 infection. J Immunol 2005; 175(2):1100–1106.

    PubMed  CAS  Google Scholar 

  24. Harle P, Noisakran S, Carr DJ. The application of a plasmid DNA encoding IFN-alpha 1 postinfection enhances cumulative survival of herpes simplex virus type 2 vaginally infected mice. J Immunol 2001; 166(3):1803–1812.

    PubMed  CAS  Google Scholar 

  25. Carr DJ, Tomanek L, Silverman RH, Campbell IL, Williams BR. RNA-dependent protein kinase is required for alpha-1 interferon transgene-induced resistance to genital herpes simplex virus type 2. J Virol 2005; 79(14):9341–9345.

    Article  PubMed  CAS  Google Scholar 

  26. Baker DA, Plotkin SA. Enhancement of vaginal infection in mice by herpes simmplex virus type II with progesterone. Proc Soc Exp Biol Med 1978; 158:131–134.

    PubMed  CAS  Google Scholar 

  27. Parr MB, Kepple L, McDermott MR, Drew MD, Bozzola JJ, Parr EL. A mouse model for studies of mucosal immunity to vaginal infection by herpes simplex virus type 2. Lab Invest 1994; 70(3):369–380.

    PubMed  CAS  Google Scholar 

  28. Harland J, Brown SM. HSV growth, preparation, and assay. Totowa, NJ: Humana Press; 1998.

    Google Scholar 

  29. Noisakran S, Carr DJ. Plasmid DNA encoding IFNalpha 1 antagonizes herpes simplex virus type 1 ocular infection through CD4+ and CD8+ T lymphocytes. J Immunol 2000; 164(12):6435–6443.

    PubMed  CAS  Google Scholar 

  30. Harle P, Cull V, Guo L, Papin J, Lawson C, Carr DJ. Transient transfection of mouse fibroblasts with type I interferon transgenes provides various degrees of protection against herpes simplex virus infection. Antiviral Res 2002; 56(1):39–49.

    Article  PubMed  CAS  Google Scholar 

  31. Kelley KA, Pitha PM. Characterization of a mouse interferon gene locus I. Isolation of a cluster of four alpha interferon genes. Nucleic Acids Res 1985; 13(3):805–823.

    Article  PubMed  CAS  Google Scholar 

  32. Seif I, De Maeyer-Guignard J. Structure and expression of a new murine interferon-alpha gene: MuIFN-alpha I9. Gene 1986; 43(1–2):111–121.

    Article  PubMed  CAS  Google Scholar 

  33. Lawson CM, Yeow WS, Lee CM, Beilharz MW. In vivo expression of an interferon-alpha gene by intramuscular injection of naked DNA. J Interferon Cytokine Res 1997; 17(5):255–261.

    PubMed  CAS  Google Scholar 

  34. Yeow WS, Lawson CM, Beilharz MW. Antiviral activities of individual murine IFN-alpha subtypes in vivo: intramuscular injection of IFN expression constructs reduces cytomegalovirus replication. J Immunol 1998; 160(6):2932–2939.

    PubMed  CAS  Google Scholar 

  35. Halford WP, Veress LA, Gebhardt BM, Carr DJ. Innate and acquired immunity to herpes simplex virus type 1. Virology 1997; 236(2):328–337.

    Article  PubMed  CAS  Google Scholar 

  36. Harle P, Lauret E, Pitha PM, De Maeyer E, Carr DJ. Expression of human and macaque type I IFN transgenes interferes with HSV-1 replication at the transcriptional and translational levels: IFN-beta is more potent than IFN-alpha 2. Virology 2001; 290(2):237–248.

    Article  PubMed  CAS  Google Scholar 

  37. Noisakran S, Campbell IL, Carr DJ. Ectopic expression of DNA encoding IFN-alpha 1 in the cornea protects mice from herpes simplex virus type 1-induced encephalitis. J Immunol 1999; 162(7):4184–4190.

    PubMed  CAS  Google Scholar 

  38. Noisakran SJ, Carr DJ. Therapeutic efficacy of DNA encoding IFN-alpha1 against corneal HSV-1 infection. Curr Eye Res 2000; 20(5):405–412.

    Article  PubMed  CAS  Google Scholar 

  39. Noisakran S, Carr DJ. Type I interferons and herpes simplex virus infection: a naked DNA approach as a therapeutic option? Immunol Res 2001; 24(1):1–11.

    Article  PubMed  CAS  Google Scholar 

  40. Noisakran S, Carr DJ. Topical application of the cornea post-infection with plasmid DNA encoding interferon-alpha1 but not recombinant interferonalphaA reduces herpes simplex virus type 1-induced mortality in mice. J Neuroimmunol 2001; 121(1–2):49–58.

    Article  PubMed  CAS  Google Scholar 

  41. Harle P, Cull V, Agbaga MP, Silverman R, Williams BR, James C, et al. Differential effect of murine alpha/beta interferon transgenes on antagonization of herpes simplex virus type 1 replication. J Virol 2002; 76(13):6558–6567.

    Article  PubMed  CAS  Google Scholar 

  42. Donnelly JJ, Wahren B, Liu MA. DNA vaccines: progress and challenges. J Immunol 2005; 175(2):633–639.

    PubMed  CAS  Google Scholar 

  43. Bartlett EJ, Cull VS, Mowe EN, Mansfield JP, James CM. Optimization of Naked DNA Delivery for Interferon Subtype Immunotherapy in Cytomegalovirus Infection. Biol Proced Online 2003; 5:43–52.

    Article  PubMed  CAS  Google Scholar 

  44. Wang R, Doolan DL, Le TP, Hedstrom RC, Coonan KM, Charoenvit Y, et al. Induction of antigen-specific cytotoxic T lymphocytes in humans by a malaria DNA vaccine. Science 1998; 282(5388):476–480.

    Article  PubMed  CAS  Google Scholar 

  45. Tuting T, Austyn J, Storkus WJ, Falo LD Jr. The Immunology of DNA Vaccines. In: Lowrie DB, and Whalen, R. G., editor. DNA Vaccines: Methods and Protocols. Totawa, NJ: Humana Press Inc.; 2000. p. 37–64.

    Google Scholar 

  46. Mumper RJ, Ledebur HC Jr., Rolland AP, Tomlinson E. Controlled Plasmid Delivery and Gene Expression. In: Lowrie DB, and Whalen, R. G., editor. DNA Vaccines: Methods and Protocols. Totawa, NJ: Humana Press Inc.; 2000. p. 267–286.

    Google Scholar 

  47. Tan PH, Manunta M, Ardjomand N, Xue SA, Larkin DF, Haskard DO, et al. Antibody targeted gene transfer to endothelium. J Gene Med 2003; 5(4):311–323.

    Article  PubMed  CAS  Google Scholar 

  48. Liang KW, Hoffman EP, Huang L. Targeted delivery of plasmid DNA to myogenic cells via transferrinconjugated peptide nucleic acid. Mol Ther 2000; 1(3):236–243.

    Article  PubMed  CAS  Google Scholar 

  49. Sambrook J, Fritsch EF, Maniatis T. Molecular Cloning: A Laboratory Manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1989.

    Google Scholar 

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Authors and Affiliations

  1. Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Bobbie Ann Austin & Daniel J. J. Carr

  2. Division of Veterinary & Biomedical Health Science, Murdoch University, 6150, Perth, Australia

    Cassandra M. James

  3. Laboratory of Neuroendocrinoimmunology, University Medical Center, 93053, Regensburg, Germany

    Peter Härle

  4. Departments of Ophthalmology and Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Daniel J. J. Carr

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  1. Bobbie Ann Austin
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Correspondence to Daniel J. J. Carr.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Austin, B.A., James, C.M., Härle, P. et al. Direct application of plasmid DNA containing type I interferon transgenes to vaginal mucosa inhibits HSV-2 mediated mortality. Biol. Proced. Online 8, 55–62 (2006). https://doi.org/10.1251/bpo118

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  • DOI: https://doi.org/10.1251/bpo118

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