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Journal of Virology, December 2005, p. 14516-14525, Vol. 79, No. 23
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.23.14516-14525.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Herpes Simplex Virus 1 Immediate-Early and Early Gene Expression during Reactivation from Latency under Conditions That Prevent Infectious Virus Production

Jean M. Pesola,1 Jia Zhu,2,{dagger} David M. Knipe,2 and Donald M. Coen1*

Departments of Biological Chemistry and Molecular Pharmacology,1 Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 021152

Received 18 July 2005/ Accepted 12 September 2005

The program of gene expression exhibited by herpes simplex virus during productive infection of cultured cells is well established; however, less is known about the regulatory controls governing reactivation from latency in neurons. One difficulty in examining gene regulation during reactivation lies in distinguishing between events occurring in initial reactivating cells versus events occurring in secondarily infected cells. Thus, two inhibitors were employed to block production of infectious virus: acyclovir, which inhibits viral DNA synthesis, and WAY-150138, which permits viral DNA synthesis but inhibits viral DNA encapsidation. Latently infected murine ganglia were explanted in the presence of either inhibitor, and then amounts of RNA, DNA, or infectious virus were quantified. In ganglia explanted for 48 h, the levels of five immediate-early and early RNAs did not exhibit meaningful differences between acyclovir and WAY-150138 treatments when analyzed by in situ hybridization or quantitative reverse transcription-PCR. However, comparative increases in viral DNA and RNA content in untreated ganglia suggested that virus was produced before 48 h postexplant. This was confirmed by the detection of infectious virus as early as 14 h postexplant. Together, these results suggest that high levels of viral gene expression at 48 h postexplant are due largely to the production of infectious virus and subsequent spread through the tissue. These results lead to a reinterpretation of previous results indicating a role for DNA replication in immediate-early and early viral gene expression; however, it remains possible that viral gene expression is regulated differently in neurons than in cultured cells.

* Corresponding author. Mailing address: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Ave., Boston, MA 02115. Phone: (617) 432-1691. Fax: (617) 432-3833. E-mail: Don_Coen{at}hms.harvard.edu.

{dagger} Present address: Department of Laboratory Medicine, University of Washington, and Programs in Infectious Disease, Fred Hutchinson Cancer Research Center, The Rosen Building, Rm. 154, 960 Republican St., Seattle, WA 98109.

Journal of Virology, December 2005, p. 14516-14525, Vol. 79, No. 23
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.23.14516-14525.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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