Comparative Neurovirulence of Herpes Simplex Virus Type 1 Strains After Peripheral or Intracerebral Inoculation of BALB/c Mice

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Abstract
Twenty-three strains of herpes simplex virus type 1 were compared for their pathogenicity in 4-wk-old BALB/c mice after peripheral (footpad) or intracerebral inoculation. Among those strains examined were 6 clinical isolates of brain or CSF origin, 7 clinical isolates of oral or genital origin, 5 prototype laboratory strains that were passaged numerous times in culture and 5 syncytial variants capable of producing cell fusion in culture. Based on comparative LD50, the strains appeared to segregate into 1 of 3 classes of neurovirulence. Class I strains were highly virulent by both the peripheral and intracerebral inoculation routes, class II strains were highly virulent by the intracerebral route only and class III strains were highly attenuated by both routes of inoculation. In vivo growth curves for whole brain homogenates infected with class III strains revealed titers of infectious virus approaching those found in the brains of animals infected with class I or II strains. Thus, a strain-dependent variation in neural spread exists that may influence the ability of the virus to cause acute neurological disease; the amount of infectious virus present within an infected brain does not necessarily determine or reflect the clinical status of the animal. Of the clinical isolates examined, the strains recovered from brain tissue of humans after fatal episodes of encephalitis were no more neurovirulent in mice than the strains isolated from nonneural sites. Although syncytial variants were highly attenuated by the peripheral route, as a group these strains were among the most virulent when inoculated directly into the CNS.