Virulence genes in herpes simplex virus type 1 corneal infection

Herpes simplex virus type 1 (HSV-1) is a significant human pathogen infecting between 70% and 90% of any given population. Most commonly, HSV-1 infection manifests itself as the appearance of ulcerative lesions on the skin or mucosal surfaces. There is also a very high rate of clinically silent infection with HSV-1, making it difficult to prevent spread of the virus. In immunocompetent individuals, these infections are self-limiting. Occasionally, HSV-1 causes more serious, even lethal, infections, including sporadic encephalitis, neonatal HSV-1, and ocular infections. In humans, HSV-1 ocular infection generally presents as conjunctivitis, which can then proceed to epithelial keratitis or deeper corneal infection. The occurrence of keratitis is a result of primary infection and at first only involves the epithelium. Replication of the virus causes cell loss, including dendritic or disciform lesions that are evident upon calcein or rose bengal staining. Due to the capacity of HSV1 to cause latent infections, reactivation from the trigeminal ganglia, or possibly other sites, can result in recrudescent keratitis. At each episode of recurrent disease, the corneal damage increases, resulting in stromal involvement, corneal clouding, and corneal neovascularization. It is estimated that more than 500,000 people in the United States suffer from ocular HSV-1 infection, and there are approximately 24,000 new cases each year, despite the availability of several antivirals for treatment. HSV-1 corneal infection can manifest itself as epithelial or stromal keratitis. Epithelial keratitis is due primarily to replication of the virus, which results in killing of epithelial cells. Viral genes that affect cell-to-cell spread may be important in the type of lesion that develops (e.g., dendritic vs. disciform), but such genes have not been identified to date. A transient corneal clouding can occur along with epithelial infection, at least in animal models, and in the absence of immunity. This may be due to direct effects of cytokines on endothelial cell activities. The immune system does not appear to play a large role in epithelial keratitis. If an uncomplicated epithelial cell infection spreads to keratocytes deeper in the cornea, stromal keratitis can develop. In animal models, this can occur directly as a result of primary infection. In humans, stromal disease usually develops after one or more recrudescent infections. In any host–parasite interaction, three factors contribute to the outcome regarding how severe the symptoms become: innate resistance, acquired immunity, and strain of virus. The role of innate and acquired immunity in HSV infection has recently been reviewed and is discussed briefly here. Host organisms clearly have innate factors that frequently halt the infection before symptoms begin. Such factors contribute to the high rate of asymptomatic infection seen with many viruses and probably play a role in the high rate of HSV-1 acquisition in the absence of disease. Innate immunity is complex, involving physical and cellular factors, soluble components (e.g., interferon, TNF-a, NO), and the products of other unknown host genes. Innate immunity is very poorly understood, though, and is not discussed in detail in this review. Stromal keratitis is clearly an immunopathological event. It was shown many years ago that T-cells were required, and subsequent studies have confirmed the requirement for T-cells (reviewed in Refs. 7 and 11). Several hypotheses have been proposed to explain the immunopathology of HSV-1–induced stromal keratitis (HSK), and these have previously been reviewed. It should be noted that HSV-1–mediated stromal