Toxicity and neuronal infection of a HSV-1 ICP34.5 mutant in nude mice

Abstract

HSV-1 mutants in the RL-1 gene encoding the ICP34.5 protein have been demonstrated to have diminished neurovirulence in brain yet replicate as efficiently as parental virus in transformed tissue culture cells. Thus they have been proposed as candidates viruses for human brain tumor therapies. Evaluation of their replicative properties and pathogenesis within the nervous system has been limited. As most patients undergoing therapies for brain tumors are likely to be immunocompromised, it will be important to understand the pathogenesis of these viruses in immunocompromised hosts. To this end, the lateral ventricle of nude mice was injected with high (2.5 x 10(7) PFU), medium (10(5) PFU), or low dose (10(3) PFU) HSV-1 variant-1716, which has a deletion in the RL-1 gene. Ten of 10 mice died within 2-3 days following the high titer infection. Six of 19 animals with medium titer infection died within 9 days, and viral antigens were seen in ependymal cells as well as neurons within the brainstem and thalamus. Although only two of 19 animals became moribund 18 days after medium titer viral infection, many neocortical and hippocampal neurons were positive for HSV-1 antigens. However, plaque-purified viral isolates recovered from brain homogenates of these animals demonstrated no increase in pathogenicity. Nine of 20 animals died following low dose infection; six of these animals, from which tissue was analyzed, all had many HSV antigen-positive neurons in the neocortex and hippocampus. These data imply that if this type of virus is used for human brain tumor therapy immunosuppressed patients may suffer from significant viral pathogenesis outside the tumor.