Differential effects on the survival of neuronal and non-neuronal cells after infection by herpes simplex virus type 1 mutants

Replication-defective mutants of herpes simplex virus type 1 (HSV-1) are po werful tools to transfer genes into postmitotic neurons and show promise fo r gene therapy protocols in vivo. To evaluate the efficacy and safety of th ese vectors for the treatment of dearness we infected dissociated cochlear ganglia with HSV mutants defective in the immediate early genes IE 2 (5dl1. 2) or IE 3 (d120). Our results reveal striking differences in the survival of neuronal and non-neuronal cells caused by these mutants. Surprisingly, c ochlear neurons infected with 5dl1.2 at various concentrations show a signi ficant increase in survival after 2 days in culture. In contrast, many non- neuronal cells undergo apoptosis reducing cell number to less than 50%. In both neuronal and nonneuronal cell types we also observe a population of ce lls with important changes in morphology. Analysis of dissociated cochlear ganglia infected with d120 reveals a decrease of neuronal survival, whereas non-neuronal cells were almost unaffected. To further characterize and com pare the effects of 5dl1.2 and d120 we transduced central nervous system-de rived cell types including cortical neurons and astrocytes. Similarly, as o bserved for cochlear neurons, infection with 5dl1.2 results in increased su rvival of cortical neurons, whereas d120 shows cytotoxic effects. Survival of astrocytes is equally reduced by both HSV deletion mutants. We conclude that HSV-1 mutants defective in immediate early genes cause very distinct c ytopathic phenotypes depending on the cellular context. Possible reasons fo r these differences, like various patterns of cellular and viral gene expre ssion, and the implications for the use of HSV-1 vectors for gene transfer are discussed.