Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1994 Feb;68(2):689–696. doi: 10.1128/jvi.68.2.689-696.1994

Immunization with replication-defective mutants of herpes simplex virus type 1: sites of immune intervention in pathogenesis of challenge virus infection.

L A Morrison 1, D M Knipe 1
PMCID: PMC236504  PMID: 8289372

Abstract

Replication-defective mutants of herpes simplex virus type 1 (HSV-1) were used as a new means to immunize mice against HSV-1-mediated ocular infection and disease. The effects of the induced immune responses on pathogenesis of acute and latent infection by challenge virus were investigated after corneal inoculation of immunized mice with virulent HSV-1. A single subcutaneous injection of replication-defective mutant virus protected mice against development of encephalitis and keratitis. Replication of the challenge virus at the initial site of infection was lower in mice immunized with attenuated, wild-type parental virus (KOS1.1) or replication-defective mutant virus than in mice immunized with uninfected cell extract or UV-inactivated wild-type virus. Significantly, latent infection in the trigeminal ganglia was reduced in mice given one immunization with replication-defective mutant virus and was completely prevented by two immunizations. Acute replication in the trigeminal ganglia was also prevented in mice immunized twice with wild-type or mutant virus. The level of protection against infection and disease generated by immunization with replication-defective mutant viruses was comparable to that of infectious wild-type virus in all cases. In addition, T-cell proliferative and neutralizing antibody responses following immunization and corneal challenge were of similar strength in mice immunized with replication-defective mutant viruses or with wild-type virus. Thus, protein expression by forms of HSV-1 capable of only partially completing the replication cycle can induce an immune response in mice that efficiently decreases primary replication of virulent challenge virus, interferes with acute and latent infection of the nervous system, and inhibits the development of both keratitis and systemic neurologic disease.

Full text

PDF
689

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Burke R. L. Contemporary approaches to vaccination against herpes simplex virus. Curr Top Microbiol Immunol. 1992;179:137–158. doi: 10.1007/978-3-642-77247-4_9. [DOI] [PubMed] [Google Scholar]
  2. Chan W. L., Lukig M. L., Liew F. Y. Helper T cells induced by an immunopurified herpes simplex virus type I (HSV-I) 115 kilodalton glycoprotein (gB) protect mice against HSV-I infection. J Exp Med. 1985 Oct 1;162(4):1304–1318. doi: 10.1084/jem.162.4.1304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Coen D. M., Irmiere A. F., Jacobson J. G., Kerns K. M. Low levels of herpes simplex virus thymidine- thymidylate kinase are not limiting for sensitivity to certain antiviral drugs or for latency in a mouse model. Virology. 1989 Feb;168(2):221–231. doi: 10.1016/0042-6822(89)90261-4. [DOI] [PubMed] [Google Scholar]
  4. Doymaz M. Z., Rouse B. T. Immunopathology of herpes simplex virus infections. Curr Top Microbiol Immunol. 1992;179:121–136. doi: 10.1007/978-3-642-77247-4_8. [DOI] [PubMed] [Google Scholar]
  5. Drew M. D., Estrada-Correa A., Underdown B. J., McDermott M. R. Vaccination by cholera toxin conjugated to a herpes simplex virus type 2 glycoprotein D peptide. J Gen Virol. 1992 Sep;73(Pt 9):2357–2366. doi: 10.1099/0022-1317-73-9-2357. [DOI] [PubMed] [Google Scholar]
  6. Foster C. S., Sandstrom I. K., Wells P. A., Thompson P., Daigle J., Opremcak E. M. Immunomodulation of experimental murine herpes simplex keratitis: II. Glycoprotein D protection. Curr Eye Res. 1988 Nov;7(11):1051–1061. doi: 10.3109/02713688809001875. [DOI] [PubMed] [Google Scholar]
  7. Foster C. S., Tsai Y., Monroe J. G., Campbell R., Cestari M., Wetzig R., Knipe D., Greene M. I. Genetic studies on murine susceptibility to herpes simplex keratitis. Clin Immunol Immunopathol. 1986 Aug;40(2):313–325. doi: 10.1016/0090-1229(86)90036-x. [DOI] [PubMed] [Google Scholar]
  8. Gao M., Knipe D. M. Genetic evidence for multiple nuclear functions of the herpes simplex virus ICP8 DNA-binding protein. J Virol. 1989 Dec;63(12):5258–5267. doi: 10.1128/jvi.63.12.5258-5267.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gao M., Knipe D. M. Potential role for herpes simplex virus ICP8 DNA replication protein in stimulation of late gene expression. J Virol. 1991 May;65(5):2666–2675. doi: 10.1128/jvi.65.5.2666-2675.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Harbour D. A., Hill T. J., Blyth W. A. Acute and recurrent herpes simplex in several strains of mice. J Gen Virol. 1981 Jul;55(Pt 1):31–40. doi: 10.1099/0022-1317-55-1-31. [DOI] [PubMed] [Google Scholar]
  11. Irie H., Harada Y., Kataoka M., Nagamuta M., Moriya Y., Handa M., Saito M., Matsubara S., Kojima K., Sugawara Y. Efficacy of oral administration of live herpes simplex virus type 1 as a vaccine. J Virol. 1992 Apr;66(4):2428–2434. doi: 10.1128/jvi.66.4.2428-2434.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kapoor A. K., Nash A. A., Wildy P. Pathogenesis of herpes simplex virus in B cell-suppressed mice: the relative roles of cell-mediated and humoral immunity. J Gen Virol. 1982 Jul;61(Pt 50):127–131. doi: 10.1099/0022-1317-61-1-127. [DOI] [PubMed] [Google Scholar]
  13. Kapoor A. K., Nash A. A., Wildy P., Phelan J., McLean C. S., Field H. J. Pathogenesis of herpes simplex virus in congenitally athymic mice: the relative roles of cell-mediated and humoral immunity. J Gen Virol. 1982 Jun;60(Pt 2):225–233. doi: 10.1099/0022-1317-60-2-225. [DOI] [PubMed] [Google Scholar]
  14. Katz J. P., Bodin E. T., Coen D. M. Quantitative polymerase chain reaction analysis of herpes simplex virus DNA in ganglia of mice infected with replication-incompetent mutants. J Virol. 1990 Sep;64(9):4288–4295. doi: 10.1128/jvi.64.9.4288-4295.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kino Y., Eto T., Nishiyama K., Ohtomo N., Mori R. Immunogenicity of purified glycoprotein gB of herpes simplex virus. Arch Virol. 1986;89(1-4):69–80. doi: 10.1007/BF01309880. [DOI] [PubMed] [Google Scholar]
  16. Kino Y., Hayashi Y., Hayashida I., Mori R. Dissemination of herpes simplex virus in nude mice after intracutaneous inoculation and effect of antibody on the course of infection. J Gen Virol. 1982 Dec;63(2):475–479. doi: 10.1099/0022-1317-63-2-475. [DOI] [PubMed] [Google Scholar]
  17. Knipe D. M., Spang A. E. Definition of a series of stages in the association of two herpesviral proteins with the cell nucleus. J Virol. 1982 Jul;43(1):314–324. doi: 10.1128/jvi.43.1.314-324.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Knotts F. B., Cook M. L., Stevens J. G. Pathogenesis of herpetic encephalitis in mice after ophthalmic inoculation. J Infect Dis. 1974 Jul;130(1):16–27. doi: 10.1093/infdis/130.1.16. [DOI] [PubMed] [Google Scholar]
  19. Martin S., Cantin E., Rouse B. T. Evaluation of antiviral immunity using vaccinia virus recombinants expressing cloned genes for herpes simplex virus type 1 glycoproteins. J Gen Virol. 1989 Jun;70(Pt 6):1359–1370. doi: 10.1099/0022-1317-70-6-1359. [DOI] [PubMed] [Google Scholar]
  20. Martin S., Courtney R. J., Fowler G., Rouse B. T. Herpes simplex virus type 1-specific cytotoxic T lymphocytes recognize virus nonstructural proteins. J Virol. 1988 Jul;62(7):2265–2273. doi: 10.1128/jvi.62.7.2265-2273.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Martin S., Zhu X. X., Silverstein S. J., Courtney R. J., Yao F., Jenkins F. J., Rouse B. T. Murine cytotoxic T lymphocytes specific for herpes simplex virus type 1 recognize the immediate early protein ICP4 but not ICP0. J Gen Virol. 1990 Oct;71(Pt 10):2391–2399. doi: 10.1099/0022-1317-71-10-2391. [DOI] [PubMed] [Google Scholar]
  22. Meignier B., Longnecker R., Roizman B. In vivo behavior of genetically engineered herpes simplex viruses R7017 and R7020: construction and evaluation in rodents. J Infect Dis. 1988 Sep;158(3):602–614. doi: 10.1093/infdis/158.3.602. [DOI] [PubMed] [Google Scholar]
  23. Mercadal C. M., Bouley D. M., DeStephano D., Rouse B. T. Herpetic stromal keratitis in the reconstituted scid mouse model. J Virol. 1993 Jun;67(6):3404–3408. doi: 10.1128/jvi.67.6.3404-3408.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mertz G. J., Ashley R., Burke R. L., Benedetti J., Critchlow C., Jones C. C., Corey L. Double-blind, placebo-controlled trial of a herpes simplex virus type 2 glycoprotein vaccine in persons at high risk for genital herpes infection. J Infect Dis. 1990 Apr;161(4):653–660. doi: 10.1093/infdis/161.4.653. [DOI] [PubMed] [Google Scholar]
  25. Mester J. C., Glorioso J. C., Rouse B. T. Protection against zosteriform spread of herpes simplex virus by monoclonal antibodies. J Infect Dis. 1991 Feb;163(2):263–269. doi: 10.1093/infdis/163.2.263. [DOI] [PubMed] [Google Scholar]
  26. Mester J. C., Rouse B. T. The mouse model and understanding immunity to herpes simplex virus. Rev Infect Dis. 1991 Nov-Dec;13 (Suppl 11):S935–S945. doi: 10.1093/clind/13.supplement_11.s935. [DOI] [PubMed] [Google Scholar]
  27. Nash A. A., Phelan J., Wildy P. Cell-mediated immunity in herpes simplex virus-infected mice: H-2 mapping of the delayed-type hypersensitivity response and the antiviral T cell response. J Immunol. 1981 Apr;126(4):1260–1262. [PubMed] [Google Scholar]
  28. Nguyen L. H., Knipe D. M., Finberg R. W. Replication-defective mutants of herpes simplex virus (HSV) induce cellular immunity and protect against lethal HSV infection. J Virol. 1992 Dec;66(12):7067–7072. doi: 10.1128/jvi.66.12.7067-7072.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Oakes J. E. Role for cell-mediated immunity in the resistance of mice to subcutaneous herpes simplex virus infection. Infect Immun. 1975 Jul;12(1):166–172. doi: 10.1128/iai.12.1.166-172.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rager-Zisman B., Allison A. C. Mechanism of immunologic resistance to herpes simplex virus 1 (HSV-1) infection. J Immunol. 1976 Jan;116(1):35–40. [PubMed] [Google Scholar]
  31. Rice S. A., Knipe D. M. Genetic evidence for two distinct transactivation functions of the herpes simplex virus alpha protein ICP27. J Virol. 1990 Apr;64(4):1704–1715. doi: 10.1128/jvi.64.4.1704-1715.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Roizman B. Introduction: objectives of herpes simplex virus vaccines seen from a historical perspective. Rev Infect Dis. 1991 Nov-Dec;13 (Suppl 11):S892–S894. doi: 10.1093/clind/13.supplement_11.s892. [DOI] [PubMed] [Google Scholar]
  33. Sandstrom I. K., Foster C. S., Wells P. A., Knipe D., Caron L., Greene M. I. Previous immunization of mice with herpes simplex virus type-1 strain MP protects against secondary corneal infection. Clin Immunol Immunopathol. 1986 Aug;40(2):326–334. doi: 10.1016/0090-1229(86)90037-1. [DOI] [PubMed] [Google Scholar]
  34. Schrier R. D., Pizer L. I., Moorhead J. W. Type-specific delayed hypersensitivity and protective immunity induced by isolated herpes simplex virus glycoprotein. J Immunol. 1983 Mar;130(3):1413–1418. [PubMed] [Google Scholar]
  35. Shepard A. A., DeLuca N. A. Intragenic complementation among partial peptides of herpes simplex virus regulatory protein ICP4. J Virol. 1989 Mar;63(3):1203–1211. doi: 10.1128/jvi.63.3.1203-1211.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Simmons A., Nash A. A. Effect of B cell suppression on primary infection and reinfection of mice with herpes simplex virus. J Infect Dis. 1987 Apr;155(4):649–654. doi: 10.1093/infdis/155.4.649. [DOI] [PubMed] [Google Scholar]
  37. Simmons A., Nash A. A. Role of antibody in primary and recurrent herpes simplex virus infection. J Virol. 1985 Mar;53(3):944–948. doi: 10.1128/jvi.53.3.944-948.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Simmons A., Tscharke D. C. Anti-CD8 impairs clearance of herpes simplex virus from the nervous system: implications for the fate of virally infected neurons. J Exp Med. 1992 May 1;175(5):1337–1344. doi: 10.1084/jem.175.5.1337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Thompson P., Wells P. A., Sandstrom I. K., Opremcak E. M., Millin J. A., Daigle J. A., Foster C. S. Immunomodulation of experimental murine herpes simplex keratitis: I. UV-HSV protection. Curr Eye Res. 1988 Nov;7(11):1043–1049. doi: 10.3109/02713688809001874. [DOI] [PubMed] [Google Scholar]
  40. Tigges M. A., Koelle D., Hartog K., Sekulovich R. E., Corey L., Burke R. L. Human CD8+ herpes simplex virus-specific cytotoxic T-lymphocyte clones recognize diverse virion protein antigens. J Virol. 1992 Mar;66(3):1622–1634. doi: 10.1128/jvi.66.3.1622-1634.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Tullo A. B., Shimeld C., Blyth W. A., Hill T. J., Easty D. L. Ocular infection with herpes simplex virus in nonimmune and immune mice. Arch Ophthalmol. 1983 Jun;101(6):961–964. doi: 10.1001/archopht.1983.01040010961023. [DOI] [PubMed] [Google Scholar]
  42. Watari E., Dietzschold B., Szokan G., Heber-Katz E. A synthetic peptide induces long-term protection from lethal infection with herpes simplex virus 2. J Exp Med. 1987 Feb 1;165(2):459–470. doi: 10.1084/jem.165.2.459. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES