Herpes Simplex Virus 1 ICP22 but Not U S 1.5 Is Required for Efficient Acute Replication in Mice and VICE Domain Formation

Abstract

The herpes simplex virus 1 (HSV-1) immediate-early protein, infected cell protein 22 (ICP22), is required for efficient replication in restrictive cells, for virus-induced chaperone-enriched (VICE) domain formation, and for normal expression of a subset of viral late proteins. Additionally, ICP22 is important for optimal acute viral replication in vivo . Previous studies have shown that the U S 1 gene that encodes ICP22, produces an in-frame, N-terminally truncated form of ICP22, known as U S 1.5. To date, studies conducted to characterize the functions of ICP22 have not separated its functions from those of U S 1.5. To determine the individual roles of ICP22 and U S 1.5, we made viral mutants that express either ICP22 with an M90A mutation in the U S 1.5 initiation codon (M90A) or U S 1.5 with three stop codons introduced upstream of the U S 1.5 start codon (3×stop). Our studies showed that, in contrast to M90A, 3×stop was unable to replicate efficiently in the eyes and trigeminal ganglia of mice during acute infection, to efficiently establish a latent infection, or to induce VICE domain formation and was only mildly reduced in its replication in restrictive HEL-299 cells and murine embryonic fibroblasts (MEFs). Both mutants enhanced the expression of the late viral proteins virion host shutoff (vhs) and glycoprotein C (gC) and inhibited viral gene expression mediated by HSV-1 infected cell protein 0 (ICP0). When we tested our mutants' sensitivity to type I interferon (beta interferon [IFN-β]) in restrictive cells, we noticed that the plating of the ICP22 null (d22) and 3×stop mutants was reduced by the addition of IFN-β. Overall, our data suggest that U S 1.5 partially complements the functions of ICP22.