Interferons regulate the phenotype of wild-type and mutant herpes simplex viruses in vivo

Mechanisms responsible for neuroattenuation of herpes simplex virus (HSV) h ave been defined previously by studies of mutant viruses in cultured cells. The hypothesis that null mutations in host genes can override the attenuat ed phenotype of null mutations in certain viral genes was tested. Mutants s uch as those in infected cell protein (ICP) 0, thymidine kinase, ribonucleo tide reductase, virion host shutoff, and ICP34.5 are reduced in their capac ity to replicate in nondividing cells in culture and in vivo. The replicati on of these viruses was examined in eyes and trigeminal ganglia for 1-7 d a fter corneal inoculation in mice with null mutations (-/-) in interferon re ceptors (IFNR) for type I IFNs (IFN-alpha/beta R), type If IFN (IFN-gamma R ), and both type I and type II IFNs (IFN-alpha/beta/gamma R). Viral titers in eyes and ganglia of IFN-gamma R-/- mice were not significantly different fi-om congenic controls. However, in IFN-alpha/beta R-/- or IFN-alpha/beta /gamma R-/- mice, growth of all mutants, including those with significantly impaired growth in cell culture, was enhanced by up to 1,000-fold in eyes and trigeminal ganglia. Blepharitis and clinical signs of infection were ev ident in IFN-alpha/beta R-/- and IFN-alpha/beta/gamma R-/- but not control mice for all viruses. Also, IFNs were shown to significantly reduce product ive infection of, and spread from intact, but not scarified, corneas. Parti cularly striking, was restoration of near-normal trigeminal ganglion replic ation and neurovirulence of an ICP34.5 mutant in IFN-alpha/beta R-/- mice. These data show that IFNs play a major role in limiting mutant and wild-typ e HSV replication in the cornea and in the nervous system. In addition, the in vivo target of ICP34.5 may be host IFN responses. These experiments dem onstrate an unsuspected role for host factors in defining the phenotypes of some HSV mutants in vivo. The phenotypes of mutant viruses therefore canno t be interpreted based solely upon studies in cell culture but must be cons idered carefully in the context of host factors that may define the in vivo phenotype.