Ribonucleotide Reductase and the Ocular Virulence of Herpes Simplex Virus Type 1

Abstract

Herpes simplex virus (HSV) type 1 infections of the eye affect approximately 500 000 people in the United States of America each year and are the leading cause of blindness due to infectious disease in developed countries. Several factors, including the strain of virus, the host immune response, and innate host resistance affect the severity of the infection. The fact that the strain of virus is important indicates that genes in the virus affect virulence. Little is known about the genetics of ocular HSV virulence. The viral thymidine kinase, ICP0, and possibly glycoprotein C genes have been reported to be involved in ocular virulence. We have been studying the role of the HSV ribonucleotide reductase (RR) gene in ocular infections using a null (deletion) mutant (ICP6Δ). The ICP6Δ deletion mutant was unable to cause blinding eye disease in our murine model of HSV keratitis compared to the parent HSV-1 KOS and a genetically engineered revertant (ICP6Δ+3.1). These results indicate that HSV-1 RR is a virulence determinant. ICP6Δ grew poorly in mouse and human corneal fibroblasts and in the mouse eye when compared to HSV-1 KOS and ICP6Δ+3.1, suggesting that the role of the HSV-1 RR is to enhance growth in the animal. RR may therefore be a valid target for new antiviral drugs. Mutants lacking the viral RR gene may also be useful as vaccine strains and vectors for neuronal gene therapy.