Abstract
Mutants of herpes simplex virus (HSV) have been used to show that a variety of key genes associated with initiation of lytic infection or replication of viral DNA are not essential for establishment of latency. These observations are extended in the present study, in which a virulent strain of HSV type 1 that is not compromised in its ability to productively infect neurons under favorable conditions was used to demonstrate early divergence of molecular pathways leading to productive and latent infection. Our experimental strategy made unique use of the segmental innervation of the vertebrate trunk to study the spread of virus throughout the peripheral nervous system after inoculation of mouse flanks. Evidence of viral gene expression, including that of immediate-early genes, was transient, confined to ganglia directly innervating the inoculated skin (8th through 12th thoracic segments), and seen only at sites from which infectious virus could be recovered. In contrast, neurons containing latency-associated transcripts and reactivatable virus were more widely distributed (sixth thoracic through first lumbar segments), from which we conclude that replication-competent HSV type 1 can establish latency without initiating productive infection.
Full text
PDF![4001](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476d/248830/65dc38224275/jvirol00051-0041.png)
![4002](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476d/248830/6ff96f64323d/jvirol00051-0042.png)
![4003](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476d/248830/44b686b3fc91/jvirol00051-0043.png)
![4004](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476d/248830/5b0ef86f2af3/jvirol00051-0044.png)
![4005](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/476d/248830/85af36b0e729/jvirol00051-0045.png)
Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Cabrera C. V., Wohlenberg C., Openshaw H., Rey-Mendez M., Puga A., Notkins A. L. Herpes simplex virus DNA sequences in the CNS of latently infected mice. Nature. 1980 Nov 20;288(5788):288–290. doi: 10.1038/288288a0. [DOI] [PubMed] [Google Scholar]
- Conley A. J., Knipe D. M., Jones P. C., Roizman B. Molecular genetics of herpes simplex virus. VII. Characterization of a temperature-sensitive mutant produced by in vitro mutagenesis and defective in DNA synthesis and accumulation of gamma polypeptides. J Virol. 1981 Jan;37(1):191–206. doi: 10.1128/jvi.37.1.191-206.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cook M. L., Stevens J. G. Pathogenesis of herpetic neuritis and ganglionitis in mice: evidence for intra-axonal transport of infection. Infect Immun. 1973 Feb;7(2):272–288. doi: 10.1128/iai.7.2.272-288.1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Efstathiou S., Minson A. C., Field H. J., Anderson J. R., Wildy P. Detection of herpes simplex virus-specific DNA sequences in latently infected mice and in humans. J Virol. 1986 Feb;57(2):446–455. doi: 10.1128/jvi.57.2.446-455.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hall P. A., Stearn P. M., Butler M. G., D'Ardenne A. J. Acetone/periodate-lysine-paraformaldehyde (PLP) fixation and improved morphology of cryostat sections for immunohistochemistry. Histopathology. 1987 Jan;11(1):93–101. [PubMed] [Google Scholar]
- 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]
- Hill T. J., Field H. J., Blyth W. A. Acute and recurrent infection with herpes simplex virus in the mouse: a model for studying latency and recurrent disease. J Gen Virol. 1975 Sep;28(3):341–353. doi: 10.1099/0022-1317-28-3-341. [DOI] [PubMed] [Google Scholar]
- KAPLAN A. S. A study of the herpes simplex virus-rabbit kidney cell system by the plaque technique. Virology. 1957 Dec;4(3):435–457. doi: 10.1016/0042-6822(57)90078-8. [DOI] [PubMed] [Google Scholar]
- 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]
- Leib D. A., Coen D. M., Bogard C. L., Hicks K. A., Yager D. R., Knipe D. M., Tyler K. L., Schaffer P. A. Immediate-early regulatory gene mutants define different stages in the establishment and reactivation of herpes simplex virus latency. J Virol. 1989 Feb;63(2):759–768. doi: 10.1128/jvi.63.2.759-768.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rock D. L., Fraser N. W. Detection of HSV-1 genome in central nervous system of latently infected mice. Nature. 1983 Apr 7;302(5908):523–525. doi: 10.1038/302523a0. [DOI] [PubMed] [Google Scholar]
- Showalter S. D., Zweig M., Hampar B. Monoclonal antibodies to herpes simplex virus type 1 proteins, including the immediate-early protein ICP 4. Infect Immun. 1981 Dec;34(3):684–692. doi: 10.1128/iai.34.3.684-692.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Simmons A., La Vista A. B. Neural infection in mice after cutaneous inoculation with HSV-1 is under complex host genetic control. Virus Res. 1989 Jul;13(3):263–270. doi: 10.1016/0168-1702(89)90020-8. [DOI] [PubMed] [Google Scholar]
- 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]
- Simmons A., Nash A. A. Zosteriform spread of herpes simplex virus as a model of recrudescence and its use to investigate the role of immune cells in prevention of recurrent disease. J Virol. 1984 Dec;52(3):816–821. doi: 10.1128/jvi.52.3.816-821.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stevens J. G., Cook M. L. Latent herpes simplex virus in spinal ganglia of mice. Science. 1971 Aug 27;173(3999):843–845. doi: 10.1126/science.173.3999.843. [DOI] [PubMed] [Google Scholar]
- 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]
- Ugolini G., Kuypers H. G., Simmons A. Retrograde transneuronal transfer of herpes simplex virus type 1 (HSV 1) from motoneurones. Brain Res. 1987 Oct 6;422(2):242–256. doi: 10.1016/0006-8993(87)90931-0. [DOI] [PubMed] [Google Scholar]
- Ugolini G., Kuypers H. G., Strick P. L. Transneuronal transfer of herpes virus from peripheral nerves to cortex and brainstem. Science. 1989 Jan 6;243(4887):89–91. doi: 10.1126/science.2536188. [DOI] [PubMed] [Google Scholar]