Replication of Herpes Simplex Virus 1 Depends on the γ 1 34.5 Functions That Facilitate Virus Response to Interferon and Egress in the Different Stages of Productive Infection

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Abstract
The ability of the γ134.5 protein to suppress the PKR response plays a crucial role in herpes simplex virus pathogenesis. In this process, the γ134.5 protein associates with protein phosphatase 1 to form a large complex that dephosphorylates eIF-2α and thereby prevents translation shutoff mediated by PKR. Accordingly, γ134.5 null mutants are virulent in PKR-knockout mice but not in wild-type mice. However, γ134.5 deletion mutants, with an extragenic compensatory mutation, inhibit PKR activity but remain avirulent, suggesting that the γ134.5 protein has additional functions. Here, we show that a substitution of the γ134.5 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 γ134.5 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 γ134.5 protein lead to a significant decrease in virus growth in mouse 3T6 cells, which is independent of eIF-2α 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 γ134.5 functions required to prevent the PKR response and to facilitate virus egress in the different stages during virus infection.

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