Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1992 Apr;66(4):2157–2169. doi: 10.1128/jvi.66.4.2157-2169.1992

Herpes simplex virus type 1 latency-associated transcription unit promotes anatomical site-dependent establishment and reactivation from latency.

N M Sawtell 1, R L Thompson 1
PMCID: PMC289008  PMID: 1312626

Abstract

Defined herpes simplex virus type 1 (HSV-1) mutants KOS/1 and KOS/62 (positive and negative, respectively, for latency-associated transcripts [LATs]) express the Escherichia coli beta-galactosidase (beta-Gal) gene during latency. These mutants were employed to assess the functions of the latency-associated transcription unit on establishment and maintenance of and reactivation from the latent state. It was found that in the trigeminal ganglia, the frequencies of hyperthermia-induced reactivation of KOS/62 and an additional LATs- mutant (KOS/29) were reduced by at least 80%. Quantification of latently infected neurons expressing the beta-Gal gene revealed that the LATs- mutant KOS/62 established approximately 80% fewer latent infections in the trigeminal ganglia than did KOS/1 (LATs+). This reduction in establishment which is evident in the trigeminal ganglia could account for the reduced frequency of reactivation from this site. In striking contrast, both LATs- mutants reactivated with wild-type frequencies from lumbosacral ganglia. Quantification of beta-Gal-positive neurons at this site revealed that KOS/62 established as many as or more latent infections than the LATs+ virus, KOS/1. Colocalization of HSV antigen and beta-Gal suggested that the decreased establishment by LATs- mutants in trigeminal ganglia was the result of inefficient viral shutoff. Thus, one function of the HSV-1 LATs transcription unit is to promote the establishment of latency in trigeminal but not lumbosacral ganglia. Such a function may be relevant to understanding the distinct clinical recurrent disease patterns of HSV-1 and HSV-2.

Full text

PDF
2157

Images in this article

2160Image
on p.2160
2163Image
on p.2163
2166Image
on p.2166

Selected References

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

  1. Batchelor A. H., O'Hare P. Regulation and cell-type-specific activity of a promoter located upstream of the latency-associated transcript of herpes simplex virus type 1. J Virol. 1990 Jul;64(7):3269–3279. doi: 10.1128/jvi.64.7.3269-3279.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Block T. M., Spivack J. G., Steiner I., Deshmane S., McIntosh M. T., Lirette R. P., Fraser N. W. A herpes simplex virus type 1 latency-associated transcript mutant reactivates with normal kinetics from latent infection. J Virol. 1990 Jul;64(7):3417–3426. doi: 10.1128/jvi.64.7.3417-3426.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Costa R. H., Draper K. G., Devi-Rao G., Thompson R. L., Wagner E. K. Virus-induced modification of the host cell is required for expression of the bacterial chloramphenicol acetyltransferase gene controlled by a late herpes simplex virus promoter (VP5). J Virol. 1985 Oct;56(1):19–30. doi: 10.1128/jvi.56.1.19-30.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Croen K. D., Ostrove J. M., Dragovic L. J., Smialek J. E., Straus S. E. Latent herpes simplex virus in human trigeminal ganglia. Detection of an immediate early gene "anti-sense" transcript by in situ hybridization. N Engl J Med. 1987 Dec 3;317(23):1427–1432. doi: 10.1056/NEJM198712033172302. [DOI] [PubMed] [Google Scholar]
  5. Croen K. D., Ostrove J. M., Dragovic L. J., Straus S. E. Patterns of gene expression and sites of latency in human nerve ganglia are different for varicella-zoster and herpes simplex viruses. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9773–9777. doi: 10.1073/pnas.85.24.9773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Deatly A. M., Spivack J. G., Lavi E., Fraser N. W. RNA from an immediate early region of the type 1 herpes simplex virus genome is present in the trigeminal ganglia of latently infected mice. Proc Natl Acad Sci U S A. 1987 May;84(10):3204–3208. doi: 10.1073/pnas.84.10.3204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Devi-Rao G. B., Goodart S. A., Hecht L. M., Rochford R., Rice M. K., Wagner E. K. Relationship between polyadenylated and nonpolyadenylated herpes simplex virus type 1 latency-associated transcripts. J Virol. 1991 May;65(5):2179–2190. doi: 10.1128/jvi.65.5.2179-2190.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dobson A. T., Sederati F., Devi-Rao G., Flanagan W. M., Farrell M. J., Stevens J. G., Wagner E. K., Feldman L. T. Identification of the latency-associated transcript promoter by expression of rabbit beta-globin mRNA in mouse sensory nerve ganglia latently infected with a recombinant herpes simplex virus. J Virol. 1989 Sep;63(9):3844–3851. doi: 10.1128/jvi.63.9.3844-3851.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Draper K. G., Devi-Rao G., Costa R. H., Blair E. D., Thompson R. L., Wagner E. K. Characterization of the genes encoding herpes simplex virus type 1 and type 2 alkaline exonucleases and overlapping proteins. J Virol. 1986 Mar;57(3):1023–1036. doi: 10.1128/jvi.57.3.1023-1036.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Farrell M. J., Dobson A. T., Feldman L. T. Herpes simplex virus latency-associated transcript is a stable intron. Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):790–794. doi: 10.1073/pnas.88.3.790. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Herold B. C., WuDunn D., Soltys N., Spear P. G. Glycoprotein C of herpes simplex virus type 1 plays a principal role in the adsorption of virus to cells and in infectivity. J Virol. 1991 Mar;65(3):1090–1098. doi: 10.1128/jvi.65.3.1090-1098.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hill J. M., Sedarati F., Javier R. T., Wagner E. K., Stevens J. G. Herpes simplex virus latent phase transcription facilitates in vivo reactivation. Virology. 1990 Jan;174(1):117–125. doi: 10.1016/0042-6822(90)90060-5. [DOI] [PubMed] [Google Scholar]
  13. Ho D. Y., Mocarski E. S. Herpes simplex virus latent RNA (LAT) is not required for latent infection in the mouse. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7596–7600. doi: 10.1073/pnas.86.19.7596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Izumi K. M., McKelvey A. M., Devi-Rao G., Wagner E. K., Stevens J. G. Molecular and biological characterization of a type 1 herpes simplex virus (HSV-1) specifically deleted for expression of the latency-associated transcript (LAT). Microb Pathog. 1989 Aug;7(2):121–134. doi: 10.1016/0882-4010(89)90031-4. [DOI] [PubMed] [Google Scholar]
  15. Javier R. T., Stevens J. G., Dissette V. B., Wagner E. K. A herpes simplex virus transcript abundant in latently infected neurons is dispensable for establishment of the latent state. Virology. 1988 Sep;166(1):254–257. doi: 10.1016/0042-6822(88)90169-9. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Krause P. R., Croen K. D., Ostrove J. M., Straus S. E. Structural and kinetic analyses of herpes simplex virus type 1 latency-associated transcripts in human trigeminal ganglia and in cell culture. J Clin Invest. 1990 Jul;86(1):235–241. doi: 10.1172/JCI114689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Krause P. R., Croen K. D., Straus S. E., Ostrove J. M. Detection and preliminary characterization of herpes simplex virus type 1 transcripts in latently infected human trigeminal ganglia. J Virol. 1988 Dec;62(12):4819–4823. doi: 10.1128/jvi.62.12.4819-4823.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Leib D. A., Bogard C. L., Kosz-Vnenchak M., Hicks K. A., Coen D. M., Knipe D. M., Schaffer P. A. A deletion mutant of the latency-associated transcript of herpes simplex virus type 1 reactivates from the latent state with reduced frequency. J Virol. 1989 Jul;63(7):2893–2900. doi: 10.1128/jvi.63.7.2893-2900.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Leib D. A., Nadeau K. C., Rundle S. A., Schaffer P. A. The promoter of the latency-associated transcripts of herpes simplex virus type 1 contains a functional cAMP-response element: role of the latency-associated transcripts and cAMP in reactivation of viral latency. Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):48–52. doi: 10.1073/pnas.88.1.48. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. McGeoch D. J. The genomes of the human herpesviruses: contents, relationships, and evolution. Annu Rev Microbiol. 1989;43:235–265. doi: 10.1146/annurev.mi.43.100189.001315. [DOI] [PubMed] [Google Scholar]
  22. Mitchell W. J., Deshmane S. L., Dolan A., McGeoch D. J., Fraser N. W. Characterization of herpes simplex virus type 2 transcription during latent infection of mouse trigeminal ganglia. J Virol. 1990 Nov;64(11):5342–5348. doi: 10.1128/jvi.64.11.5342-5348.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mitchell W. J., Lirette R. P., Fraser N. W. Mapping of low abundance latency-associated RNA in the trigeminal ganglia of mice latently infected with herpes simplex virus type 1. J Gen Virol. 1990 Jan;71(Pt 1):125–132. doi: 10.1099/0022-1317-71-1-125. [DOI] [PubMed] [Google Scholar]
  24. Mitchell W. J., Steiner I., Brown S. M., MacLean A. R., Subak-Sharpe J. H., Fraser N. W. A herpes simplex virus type 1 variant, deleted in the promoter region of the latency-associated transcripts, does not produce any detectable minor RNA species during latency in the mouse trigeminal ganglion. J Gen Virol. 1990 Apr;71(Pt 4):953–957. doi: 10.1099/0022-1317-71-4-953. [DOI] [PubMed] [Google Scholar]
  25. Mogensen S. C., Teisner B., Andersen H. K. Focal necrotic hepatitis in mice as a biological marker for differentiation of Herpesvirus hominis type 1 and type 2. J Gen Virol. 1974 Oct;25(1):151–155. doi: 10.1099/0022-1317-25-1-151. [DOI] [PubMed] [Google Scholar]
  26. Mogensen S. Role of macrophages in hepatitis induced by Herpes simplex virus types 1 and 2 in mice. Infect Immun. 1977 Mar;15(3):686–691. doi: 10.1128/iai.15.3.686-691.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Plummer G., Waner J. L., Bowling C. P. Comparative studies of type 1 and type 2 & 'herpes simplex' viruses. Br J Exp Pathol. 1968 Apr;49(2):202–208. [PMC free article] [PubMed] [Google Scholar]
  28. Plummer G., Waner J. L., Phuangsab A., Goodheart C. R. Type 1 and type 2 herpes simplex viruses: serological and biological differences. J Virol. 1970 Jan;5(1):51–59. doi: 10.1128/jvi.5.1.51-59.1970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Reeves W. C., Corey L., Adams H. G., Vontver L. A., Holmes K. K. Risk of recurrence after first episodes of genital herpes. Relation to HSV type and antibody response. N Engl J Med. 1981 Aug 6;305(6):315–319. doi: 10.1056/NEJM198108063050604. [DOI] [PubMed] [Google Scholar]
  30. Rock D. L., Nesburn A. B., Ghiasi H., Ong J., Lewis T. L., Lokensgard J. R., Wechsler S. L. Detection of latency-related viral RNAs in trigeminal ganglia of rabbits latently infected with herpes simplex virus type 1. J Virol. 1987 Dec;61(12):3820–3826. doi: 10.1128/jvi.61.12.3820-3826.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Sawtell N. M., Thompson R. L. Rapid in vivo reactivation of herpes simplex virus in latently infected murine ganglionic neurons after transient hyperthermia. J Virol. 1992 Apr;66(4):2150–2156. doi: 10.1128/jvi.66.4.2150-2156.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sedarati F., Izumi K. M., Wagner E. K., Stevens J. G. Herpes simplex virus type 1 latency-associated transcription plays no role in establishment or maintenance of a latent infection in murine sensory neurons. J Virol. 1989 Oct;63(10):4455–4458. doi: 10.1128/jvi.63.10.4455-4458.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Spivack J. G., Fraser N. W. Expression of herpes simplex virus type 1 latency-associated transcripts in the trigeminal ganglia of mice during acute infection and reactivation of latent infection. J Virol. 1988 May;62(5):1479–1485. doi: 10.1128/jvi.62.5.1479-1485.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Steiner I., Spivack J. G., Lirette R. P., Brown S. M., MacLean A. R., Subak-Sharpe J. H., Fraser N. W. Herpes simplex virus type 1 latency-associated transcripts are evidently not essential for latent infection. EMBO J. 1989 Feb;8(2):505–511. doi: 10.1002/j.1460-2075.1989.tb03404.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Steiner I., Spivack J. G., O'Boyle D. R., 2nd, Lavi E., Fraser N. W. Latent herpes simplex virus type 1 transcription in human trigeminal ganglia. J Virol. 1988 Sep;62(9):3493–3496. doi: 10.1128/jvi.62.9.3493-3496.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Stevens J. G. Human herpesviruses: a consideration of the latent state. Microbiol Rev. 1989 Sep;53(3):318–332. doi: 10.1128/mr.53.3.318-332.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Stevens J. G., Wagner E. K., Devi-Rao G. B., Cook M. L., Feldman L. T. RNA complementary to a herpesvirus alpha gene mRNA is prominent in latently infected neurons. Science. 1987 Feb 27;235(4792):1056–1059. doi: 10.1126/science.2434993. [DOI] [PubMed] [Google Scholar]
  38. Thompson R. L., Cook M. L., Devi-Rao G. B., Wagner E. K., Stevens J. G. Functional and molecular analyses of the avirulent wild-type herpes simplex virus type 1 strain KOS. J Virol. 1986 Apr;58(1):203–211. doi: 10.1128/jvi.58.1.203-211.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Thompson R. L., Rogers S. K., Zerhusen M. A. Herpes simplex virus neurovirulence and productive infection of neural cells is associated with a function which maps between 0.82 and 0.832 map units on the HSV genome. Virology. 1989 Oct;172(2):435–450. doi: 10.1016/0042-6822(89)90186-4. [DOI] [PubMed] [Google Scholar]
  40. Thompson R. L., Stevens J. G. Biological characterization of a herpes simplex virus intertypic recombinant which is completely and specifically non-neurovirulent. Virology. 1983 Nov;131(1):171–179. doi: 10.1016/0042-6822(83)90543-3. [DOI] [PubMed] [Google Scholar]
  41. Wagner E. K., Flanagan W. M., Devi-Rao G., Zhang Y. F., Hill J. M., Anderson K. P., Stevens J. G. The herpes simplex virus latency-associated transcript is spliced during the latent phase of infection. J Virol. 1988 Dec;62(12):4577–4585. doi: 10.1128/jvi.62.12.4577-4585.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Wechsler S. L., Nesburn A. B., Watson R., Slanina S. M., Ghiasi H. Fine mapping of the latency-related gene of herpes simplex virus type 1: alternative splicing produces distinct latency-related RNAs containing open reading frames. J Virol. 1988 Nov;62(11):4051–4058. doi: 10.1128/jvi.62.11.4051-4058.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Wheatley S. C., Kemp L. M., Wood J. N., Latchman D. S. Cell lines derived from dorsal root ganglion neurons are nonpermissive for HSV and express only the latency-associated transcript following infection. Exp Cell Res. 1990 Oct;190(2):243–246. doi: 10.1016/0014-4827(90)90192-d. [DOI] [PubMed] [Google Scholar]
  44. Zwaagstra J. C., Ghiasi H., Slanina S. M., Nesburn A. B., Wheatley S. C., Lillycrop K., Wood J., Latchman D. S., Patel K., Wechsler S. L. Activity of herpes simplex virus type 1 latency-associated transcript (LAT) promoter in neuron-derived cells: evidence for neuron specificity and for a large LAT transcript. J Virol. 1990 Oct;64(10):5019–5028. doi: 10.1128/jvi.64.10.5019-5028.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES