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Journal of Virology, October 2002, p. 9744-9755, Vol. 76, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.19.9744-9755.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

An Early Regulatory Function Required in a Cell Type-Dependent Manner Is Expressed by the Genomic but Not the cDNA Copy of the Herpes Simplex Virus 1 Gene Encoding Infected Cell Protein 0

Alice P. W. Poon,1 Saul J. Silverstein,2 and Bernard Roizman1*

Marjorie B. Kovler Viral Oncology Laboratories, The University of Chicago, Chicago, Illinois 60637,1 Department of Microbiology, College of Physicians and Surgeons, Columbia University, New York, New York 100322

Received 5 March 2002/ Accepted 19 June 2002

The {alpha}0 genes of herpes simplex virus 1 (HSV-1) contain three exons. Earlier studies have shown that the substitution of genomic sequences with a cDNA copy does not alter the capacity of the virus to replicate or establish latent infection. Other studies have demonstrated that HSV-1 may express alternatively spliced forms of {alpha}0 transcripts. The studies reported here centered on a mutant HSV-1(vCPc0) strain in which the genomic copies of the {alpha}0 gene were replaced with cDNA copies. From our research, we report the following observations. (i) In contrast to events transpiring in cells infected with wild-type virus, the expression of HSV-1(vCPc0) genes was delayed or restricted to {alpha} genes for many hours in rabbit skin cells and to a lesser extent in HEp-2 cells but not in Vero cells. This delay in the expression of HSV-1(vCPc0) ß or {gamma} genes was also multiplicity of infection dependent. (ii) Exposure to MG132, a proteasomal inhibitor, before infection with wild-type virus had no significant effect on the accumulation of viral proteins in Vero cells and caused an only slight delay in viral gene expression in rabbit skin cells in a multiplicity of infection-dependent fashion. The drug had no effect when it was added to the medium 3 h after infection. (iii) Rabbit skin or HEp-2 cells exposed to MG132 3 h after infection with the HSV-1(vCPc0) mutant accumulated only {alpha} proteins. This restriction was cell type dependent but not multiplicity of infection dependent. (iv) Both the delay in the expression of ß and {gamma} genes and the effect of MG132 added to the medium 3 h after infection were rescued by restoration of the intron 1 sequences in the HSV-1(vCPc0) mutant. However, cells transduced by baculoviruses expressing intron 1 RNA did not complement the HSV-1(vCPc0) mutant, suggesting that the function of intron 1 is in cis rather than in trans. We came to the following conclusions as a result. (i) Post-{alpha} gene expression requires the involvement of the proteasomal pathway in a cell type-dependent manner. Consistent with this requirement, the proapoptotic functions of MG132 are blocked in cells infected before exposure to the drug but not after exposure. (ii) A function encoded by the {alpha}0 gene that is absent from the cDNA copy is required for viral gene expression in a cell type- and multiplicity of infection-dependent fashion. The absence of this master function delays but does not ultimately block viral gene expression in the cell lines tested here.

* Corresponding author. Mailing address: Marjorie B. Kovler Viral Oncology Laboratories, The University of Chicago, 910 E. 58th St., Chicago, IL 60637. Phone: (773) 702-1898. Fax: (773) 702-1631. E-mail: bernard{at}cummings.uchicago.edu.

Journal of Virology, October 2002, p. 9744-9755, Vol. 76, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.19.9744-9755.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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