PROTEASE-DEFICIENT HERPES-SIMPLEX VIRUS PROTECTS MICE FROM LETHAL HERPESVIRUS-INFECTION

Null mutants and attenuated mutants of herpes simplex virus (HSV) have been shown to induce immunity against challenge from wild-type virus. Null viruses with a defect in late gene products would be expected to express more viral genes than viruses with defects in essential early gene products and thus induce a better immune response. Herpesviruses encode a late gene product (serine protease) that is autocatalytic an d cleaves the capsid assembly protein during viral replication. To det ermine whether a virus with a mutation in this gene could induce immun ity, we constructed a recombinant virus containing the gusA reporter g ene in the protease domain of the HSV type 1 UL26 open reading frame ( ORF), Consistent with previous results (M. Gao, L. Matusick-Kumar, W. Hurlburt, S. F. DiTusa, W. W. Newcomb, J. C. Brown, P. J. McCann, I. D eckman, and R. J. Colonno, J. Virol. 68:3702-3712, 1994), recombinant virus could be isolated only from helper cell lines expressing the pro duct of the UL26 ORF. Mice inoculated with the recombinant virus were unaffected by doses of virus that were lethal to mice infected with wi ld-type virus. Mice which were previously inoculated with the recombin ant virus were also protected by a subsequent challenge with wild-type virus in a dose-dependent manner. These results indicate that recombi nant viruses lacking the protease gene are avirulent but render protec tion from subsequent challenge.