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Journal of Virology, December 2004, p. 13562-13572, Vol. 78, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.24.13562-13572.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Role of the VP16-Binding Domain of vhs in Viral Growth, Host Shutoff Activity, and Pathogenesis

Departments of Ophthalmology and Visual Sciences,¹ Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri²

Received 6 April 2004/ Accepted 3 August 2004

The virion host shutoff (vhs) protein of herpes simplex virus type 1 causes the degradation of host and viral mRNA immediately upon infection of permissive cells. vhs can interact with VP16 through a 20-amino-acid binding domain, and viruses containing a deletion of this VP16-binding domain of vhs (20) and a corresponding marker rescue (20R) were constructed and characterized. Transient-transfection assays showed that this domain was dispensable for vhs activity. The 20 recombinant virus, however, was unable to induce mRNA degradation in the presence of actinomycin D, while degradation induced by 20R was equivalent to that for wild-type virus. 20, 20R, and KOS caused comparable RNA degradation in the absence of actinomycin D. Western blot analysis of infected cells indicated that comparable levels of vhs were expressed by 20, 20R, and KOS, and there was only a modest reduction of vhs packaging in 20. Immunoprecipitation of protein from cells infected with 20 and 20R showed equivalent coprecipitation of vhs and VP16. Pathogenesis studies with 20 showed a significant decrease in replication in the corneas, trigeminal ganglia, and brains, as well as a significant reduction in clinical disease and lethality, but no significant difference in the establishment of, or reactivation from, latency compared to results with KOS and 20R. These results suggest that the previously described VP16-binding domain is not required for vhs packaging or for binding to VP16. It is required, however, for RNA degradation activity of tegument-derived vhs and wild-type replication and virulence in mice.

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