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Journal of Virology, July 2004, p. 7653-7666, Vol. 78, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.14.7653-7666.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Replication of Herpes Simplex Virus 1 Depends on the {gamma}134.5 Functions That Facilitate Virus Response to Interferon and Egress in the Different Stages of Productive Infection

Xianghong Jing, Melissa Cerveny, Kui Yang, and Bin He*

Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612

Received 5 November 2003/ Accepted 5 March 2004

The ability of the {gamma}134.5 protein to suppress the PKR response plays a crucial role in herpes simplex virus pathogenesis. In this process, the {gamma}134.5 protein associates with protein phosphatase 1 to form a large complex that dephosphorylates eIF-2{alpha} and thereby prevents translation shutoff mediated by PKR. Accordingly, {gamma}134.5 null mutants are virulent in PKR-knockout mice but not in wild-type mice. However, {gamma}134.5 deletion mutants, with an extragenic compensatory mutation, inhibit PKR activity but remain avirulent, suggesting that the {gamma}134.5 protein has additional functions. Here, we show that a substitution of the {gamma}134.5 gene with the NS1 gene from influenza A virus renders viral resistance to interferon involving PKR. The virus replicates as efficiently as wild-type virus in SK-N-SH and CV-1 cells. However, in mouse 3T6 cells, the virus expressing the NS1 protein grows at an intermediate level between the wild-type virus and the {gamma}134.5 deletion mutant. This decrease in growth, compared to that of the wild-type virus, is due not to an inhibition of viral protein synthesis but rather to a block in virus release or egress. Virus particles are predominantly present in the nucleus and cytoplasm. Notably, deletions in the amino terminus of the {gamma}134.5 protein lead to a significant decrease in virus growth in mouse 3T6 cells, which is independent of eIF-2{alpha} dephosphorylation. In correlation, a series of deletions in the amino-terminal domain impair nuclear as well as cytoplasmic egress. These results indicate that efficient viral replication depends on the {gamma}134.5 functions required to prevent the PKR response and to facilitate virus egress in the different stages during virus infection.

* Corresponding author. Mailing address: Department of Microbiology and Immunology (M/C 790), College of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave., Chicago, IL 60612. Phone: (312) 996-2391. Fax: (312) 996-6415. E-mail: tshuo{at}uic.edu.

Journal of Virology, July 2004, p. 7653-7666, Vol. 78, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.14.7653-7666.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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