This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Balliet, J. W.
Right arrow Articles by Schaffer, P. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Balliet, J. W.
Right arrow Articles by Schaffer, P. A.

 Previous Article  |  Next Article 

Journal of Virology, January 2006, p. 440-450, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.440-450.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Point Mutations in Herpes Simplex Virus Type 1 oriL, but Not in oriS, Reduce Pathogenesis during Acute Infection of Mice and Impair Reactivation from Latency

John W. Balliet and Priscilla A. Schaffer*

Departments of Medicine and Microbiology and Molecular Genetics, Harvard Medical School at the Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215

Received 21 July 2005/ Accepted 12 October 2005

In vitro studies of herpes simplex virus type 1 (HSV-1) viruses containing mutations in core sequences of the viral origins of DNA replication, oriL and oriS, that eliminate the ability of these origins to initiate viral-DNA synthesis have demonstrated little or no effect on viral replication in cultured cells, leading to the conclusion that the two types of origins are functionally redundant. It remains unclear, therefore, why origins that appear to be redundant are maintained evolutionarily in HSV-1 and other neurotropic alphaherpesviruses. To test the hypothesis that oriL and oriS have distinct functions in the HSV-1 life cycle in vivo, we determined the in vivo phenotypes of two mutant viruses, DoriL-ILR and DoriS-I, containing point mutations in oriL and oriS site I, respectively, that eliminate origin DNA initiation function. Following corneal inoculation of mice, tear film titers of DoriS-I were reduced relative to wild-type virus. In all other tests, however, DoriS-I behaved like wild-type virus. In contrast, titers of DoriL-ILR in tear film, trigeminal ganglia (TG), and hindbrain were reduced and mice infected with DoriL-ILR exhibited greatly reduced mortality relative to wild-type virus. In the TG explant and TG cell culture models of reactivation, DoriL-ILR reactivated with delayed kinetics and, in the latter model, with reduced efficiency relative to wild-type virus. Rescuant viruses DoriL-ILR-R and DoriS-I-R behaved like wild-type virus in all tests. These findings demonstrate that functional differences exist between oriL and oriS and reveal a prominent role for oriL in HSV-1 pathogenesis.


* Corresponding author. Mailing address: Department of Medicine, Harvard Medical School at the Beth Israel Deaconess Medical Center, 330 Brookline Avenue, RN 123, Boston, MA 02215. Phone: (617) 667-2958. Fax: (617) 667-8540. E-mail: pschaffe{at}bidmc.harvard.edu.


Journal of Virology, January 2006, p. 440-450, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.440-450.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.




This article has been cited by other articles:

  • Bowman, J. J., Schaffer, P. A. (2009). Origin of Expression of the Herpes Simplex Virus Type 1 Protein US1.5. J. Virol. 83: 9183-9194 [Abstract] [Full Text]  
  • Khalil, M. I., Hay, J., Ruyechan, W. T. (2008). Cellular Transcription Factors Sp1 and Sp3 Suppress Varicella-Zoster Virus Origin-Dependent DNA Replication. J. Virol. 82: 11723-11733 [Abstract] [Full Text]  
  • Nagel, C.-H., Dohner, K., Fathollahy, M., Strive, T., Borst, E. M., Messerle, M., Sodeik, B. (2008). Nuclear Egress and Envelopment of Herpes Simplex Virus Capsids Analyzed with Dual-Color Fluorescence HSV1(17+). J. Virol. 82: 3109-3124 [Abstract] [Full Text]  
  • Alexander, D. E., Ward, S. L., Mizushima, N., Levine, B., Leib, D. A. (2007). Analysis of the Role of Autophagy in Replication of Herpes Simplex Virus in Cell Culture. J. Virol. 81: 12128-12134 [Abstract] [Full Text]  
  • Link, M. A., Schaffer, P. A. (2007). Herpes Simplex Virus Type 1 C-Terminal Variants of the Origin Binding Protein (OBP), OBPC-1 and OBPC-2, Cooperatively Regulate Viral DNA Levels In Vitro, and OBPC-2 Affects Mortality in Mice. J. Virol. 81: 10699-10711 [Abstract] [Full Text]  
  • Orlando, J. S., Balliet, J. W., Kushnir, A. S., Astor, T. L., Kosz-Vnenchak, M., Rice, S. A., Knipe, D. M., Schaffer, P. A. (2006). ICP22 Is Required for Wild-Type Composition and Infectivity of Herpes Simplex Virus Type 1 Virions. J. Virol. 80: 9381-9390 [Abstract] [Full Text]