The Immediate-Early Protein, ICP0, Is Essential for the Resistance of Herpes Simplex Virus to Interferon-α/β

Abstract

Herpes simplex virus type 1 (HSV-1) is resistant to the antiviral effects of interferon (IFN)-α, -β, or -γ. The fact that ICP0− mutants replicate like wild-type virus in IFN-α/β receptor knockout mice (Leib et al., 1999, J. Exp. Med. 189, 663) suggested that ICP0 may serve a direct role in the resistance of HSV-1 to IFN. To test this hypothesis, the effects of IFN-α, -β, and -γ were compared against wild-type HSV-1 and an ICP0− mutant virus, 7134. In Vero cells, 7134 was more sensitive to inhibition by low doses of type I IFN (-α/β) or type II IFN (-γ) than vesicular stomatitis virus, a well-studied IFN-sensitive virus. At a concentration of 100 U/ml, IFN-α, -β, or -γ reduced the efficiency of 7134 plaque formation by 120-, 560-, and 45-fold, respectively. In contrast, none of the IFNs reduced wild-type HSV-1 plaque formation by more than 3-fold. Even when Vero cells were infected with 10 pfu per cell, IFN-α and -β inhibited 7134 replication by over 100-fold, but inhibition by IFN-γ decreased to less than 10-fold. While IFN-β efficiently inhibited 7134 replication in primary mouse kidney and SK-N-SH cells, IFN-γ did not inhibit 7134 to a comparable extent in these cells. ICP0 provided in trans from an adenovirus vector allowed 7134 to replicate efficiently in Vero cells in the presence of IFN-α, -β, or -γ. While IFN-β or -γ efficiently repressed the ICP0 promoter-lacZ reporter gene in 7134 (i.e., ∼60-fold reduction in β-galactosidase activity), ICP0 provided in trans almost completely reversed IFN-mediated repression of the lacZ gene in 7134. The results suggest that the rate of ICP0 expression in infected cells in vivo may be critical in determining whether host IFNs repress the HSV-1 genome. This concept is discussed in light of its potential relevance to the establishment of latent HSV-1 infections.