Two Avirulent Herpes Simplex Viruses Generate Lethal Recombinants in Vivo

While it is widely appreciated that infection with a virulent virus can produce disease in an animal, the ability of a mixture of avirulent viruses to produce disease by means of complementation or recombination in vivo has not been established. In this study, two weakly neuroinvasive herpes simplex virus type 1 (HSV-1) strains were simultaneously inoculated onto the footpads of mice. Many (62%) of the animals that received a 1:1 mixture of the viruses died, whereas the animals that received a similar or 100-fold higher dose of each agent alone survived. Of fourteen viruses isolated from the brains of ten mice that died after receiving the mixture of the two weakly neuroinvasive viruses, eleven were recombinants; three of these recombinants were lethal when reapplied to the footpads of mice. These results show that two avirulent HSV-1 variants may interact in vivo to produce virulent recombinants and a lethal infection. They also suggest that different genetic lesions account for the weakly neuroinvasive character of the HSV-1 strains ANG and KOS after footpad inoculation.