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Enhanced in vitro reactivation of latent herpes simplex virus from neural and peripheral tissues with hexamethylenebisacetamide

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Summary

We evaluated the effect of the demethylating agent hexamethylenebisacetamide on reactivation of latent herpes simplex virus type 2 (HSV-2) from guinea pig neural and extraneural tissues. Four explant cultures from the dorsal root ganglia of 42 latently infected guinea pigs and vaginal and cervical explant cultures from 33 animals were divided so that half received 5 mM of hexamethylenebisacetamide supplemented media and half media alone. HSV-2 was recovered earlier and from a greater percentage of treated cultures than controls. For example, seven days after explant, HSV-2 was recovered from 35 of 84 (42%) treated dorsal root ganglia cultures compared to seven of 84 control cultures (p<0.0001). Likewise, HSV-2 was recovered seven days after explant from 11 of 66 (17%) treated external genital skin cultures and 2 of 66 control cultures (p<0.009), Hexamethylenebisacetamide had no effect on productive HSV-2 infection in guinea pig dorsal root ganglia cultures. This study provides evidence for a role of demethylation in the reactivation of latent HSV from neural as well as peripheral tissues and suggests that latent virus exists at these sites in a similar state. Hexamethylenebisacetamide should be useful in studies of herpes virus latency because it decreases the time necessary to recover virus from latently infected tissues and enhances the recovery of virus.

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References

  1. Ben-Sasson SA, Klein G (1981) Activation of the Epstein-Barr virus genome by 5-azacytidine in latently infected human lymphoid lines. Int J Cancer 28: 131–135

    Google Scholar 

  2. Breslow N (1970) Generalized Kruskall-Wallis test for comparing K samples subject to unequal patterns of censorship. Biometrika 57: 579–594

    Google Scholar 

  3. Bryson Y, Dillon M, Lovett J, Bernstein D, Sayre J (1983) A prospective long term study of the natural history of genital HSV infections: effect of ACV. In: American Society for Microbiology (eds) Programs and abstracts of the 23rd Interscience Conference on Antimicrobial Agents and Chemotherapy (Las Vegas, Nevada), Abstract 739, p 220

  4. Christman JK, Price P, Pedrinan L, Acs G (1977) Correlation between hypomethylation of DNA and expression of globin genes in Friend erythroleukaemia cells. Eur J Biochem 81: 53–61

    Google Scholar 

  5. Christy B, Scangos G (1982) Expression of transferred thymidine kinase genes is controlled by methylation. Proc Natl Acad Sci USA 79: 6299–6303

    Google Scholar 

  6. Clough DW, Kunkel LM, Davidson RL (1982) 5-azacytidine-induced reactivation of a herpes simplex thymidine kinase gene. Science 216: 70–73

    Google Scholar 

  7. Desrosiers RC, Mulder C, Fleckenstein B (1979) Methylation of Herpes Saimiri DNA in lymphoid tumor cell lines. Proc Natl Acad Sci USA 76: 3839–3843

    Google Scholar 

  8. Doerfler W (1981) DNA-methylation: a regulatory signal in eukaryotic gene expression. J Gen Virol 57: 1–20

    Google Scholar 

  9. Dressler GR, Rock DL, Fraser NW (1987) Latent herpes simplex virus type 1 DNA is not extensively methylated in vivo. J Gen Virol 68: 1761–1765

    Google Scholar 

  10. Harbour DA, Hill TJ, Blyth WA (1983) Recurrent herpes simplex in the mouse: inflammation in the skin and activation in the ganglia following peripheral stimulation. J Gen Virol 64: 1491–1498

    Google Scholar 

  11. Hill TJ (1985) Herpes simplex virus latency. In: Roizman B (ed) The herpesviruses, vol 3. Plenum Press, New York, pp 175–255

    Google Scholar 

  12. Hill JJ, Harbour DA, Blyth WA (1980) Isolation of herpes simplex virus from the skin of clinically normal mice during latent infection. J Gen Virol 47: 205–206

    Google Scholar 

  13. Hsiung GD, Tenser RB, Fong CKY (1976) Comparison of guinea pig cytomegalovirus and guinea pig herpes-like virus: growth characteristics and antigenic relationship. Infect Immun 13: 926–933

    Google Scholar 

  14. Kitchener HC, Cordiner JW, Eglin RR (1982) Latency of herpes simplex virus in uterosacral ligaments. Am J Obstet Gynecol 143: 839–840

    Google Scholar 

  15. Kolata G (1985) Fitting methylation into development. Science 228: 1183–1184

    Google Scholar 

  16. Mohandas T, Sparkes RS, Shapiro LJ (1981) Reactivation of inactive human x chromosome: evidence for x inactivation by DNA methylation. Science 211: 393–396

    Google Scholar 

  17. Openshaw H, Asher LVS, Wohlenberg C, Sekizawa T, Notkins AL (1979) Acute and latent infection of sensory ganglia with herpes simplex virus. Immune control and virus reactivation. J Gen Virol 44: 205–215

    Google Scholar 

  18. Razin A, Szyf M, Kafri T, Roll M, Giloh H, Scarpa S, Carotti D, Canton GL (1986) Replacement of 5-methylcytosine by cytosine: a possible mechanism for transient DNA demethylation during differentiation. Proc Natl Acad Sci USA 83: 2827–2831

    Google Scholar 

  19. Scriba M (1977) Extraneural localization of herpes simplex virus in latently infected guinea pigs. Science 267: 527–531

    Google Scholar 

  20. Scriba M (1981) Persistence of herpes simplex virus (HSV) infection in ganglia and peripheral tissues of guinea pigs. Med Microbiol Immunol 169: 91–96

    Google Scholar 

  21. Scriba M, Tatzber F (1981) Pathogenesis of herpes simplex virus infections in guinea pigs. Infect Immun 34: 655–661

    Google Scholar 

  22. Stanberry LR (1986) Herpesvirus latency and recurrence. Prog Med Virol 33: 61–77

    Google Scholar 

  23. Stanberry LR, Bernstein DI, Kit S, Myers MG (1986) Genital reinfection after recovery from initial genital infection with herpes simplex virus type 2 in guinea pigs. J Infect Dis 153: 1055–1061

    Google Scholar 

  24. Stanberry LR, Kern ER, Richards JT, Abott TM, Overall JC Jr (1982) Genital herpes in guinea pig: pathogenesis of the primary infection and description of recurrent disease. J Infect Dis 146: 397–404

    Google Scholar 

  25. Stanberry LR, Kern ER, Richards JT, Overall JC Jr (1985) Recurrent genital herpes simplex virus infection in guinea pigs. Intervirology 24: 226–231

    Google Scholar 

  26. Stanberry LR, Kit S, Myers MG (1985) Thymidine kinase-deficient herpes simplex virus type 2 genital infection in guinea pigs. J Virol 55: 322–328

    Google Scholar 

  27. Stephanopoulos DE, Bernstein DI (1986) 5-azacytidine reactivates herpes simplex virus (HSV) from latently infected guinea pig neural tissuesin vitro. In: American Society for Microbiology (eds) Program and abstracts of the 26rd Interscience Conference on Antimicrobial Agents and Chemotherapy, (New Orleans, Lousiana), Abstract 622, p 210

  28. Stevens JG, Cook ML (1971) Latent herpes simplex virus in spinal ganglia of mice. Science 173: 843–845

    Google Scholar 

  29. Szyf M, Eliasson L, Mann V, Klein G, Razin A (1985) Cellular and viral DNA hypomethylation associated with induction of Epstein-Barr virus lytic cycle. Proc Natl Acad Sci USA 82: 8090–8094

    Google Scholar 

  30. Taylor SM, Constantinides PA, Jones PA (1984) 5-azacytidine, DNA methylation and differentiation. Curr Top Microbiol Immunol 108: 115–127

    Google Scholar 

  31. Tobin SM, Wilson WD, Fish EN, Papsin FR (1978) Relation of herpes hominis type II to cancer of the cervix: An animal model for the introduction of long term latency of herpesvirus hominis type II. Obstet Gyn 51: 707–711

    Google Scholar 

  32. Walz MA, Price RW, Kayashi K, Katz BJ, Notkins AL (1977) Effect of immunization on acute and latent infections of vaginouterine tissue with herpes simplex virus types 1 and 2. J Infect Dis 135: 744–752

    Google Scholar 

  33. Whitby AJ, Blyth WA, Hill TJ (1982) The effect of DNA hypomethylating agents on the reactivation of herpes simplex from latently infected mouse ganglia in vitro. Arch Virol 97: 137–144

    Google Scholar 

  34. Youssoufian H, Hammer SM, Hirsch MS, Mulder C (1982) Methylation of the viral genome in anin vitro model of herpes simplex virus latency. Proc Natl Acad Sci USA 79: 2207–2210

    Google Scholar 

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  1. Clinical Virology Division, James N. Gamble Institute of Medical Research, Cincinnati, Ohio, U.S.A.

    D. I. Bernstein & J. C. Kappes

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  1. D. I. Bernstein
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  2. J. C. Kappes
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Bernstein, D.I., Kappes, J.C. Enhanced in vitro reactivation of latent herpes simplex virus from neural and peripheral tissues with hexamethylenebisacetamide. Archives of Virology 99, 57–65 (1988). https://doi.org/10.1007/BF01311023

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  • DOI: https://doi.org/10.1007/BF01311023

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