IMMUNIZATION WITH REPLICATION-DEFECTIVE MUTANTS OF HERPES-SIMPLEX VIRUS TYPE-1 - SITES OF IMMUNE INTERVENTION IN PATHOGENESIS OF CHALLENGE VIRUS-INFECTION

Replication-defective mutants of herpes simplex virus type 1 (HSV-1) w ere used as a new means to immunize mice against HSV-l-mediated ocular infection and disease. The effects of the induced immune responses on pathogenesis of acute and latent infection by challenge virus were in vestigated after corneal inoculation of immunized mice with virulent H SV-1. A single subcutaneous injection of replication-defective mutant virus protected mice against development of encephalitis and keratitis . Replication of the challenge virus at the initial site of infection was lower in mice immunized with attenuated, wild-type parental virus (KOS1.1) or replication-defective mutant virus than in mice immunized with uninfected cell extract or W-inactivated wild-type virus. Signifi cantly, latent infection in the trigeminal ganglia was reduced in mice given one immunization with replication-defective mutant virus and wa s completely prevented by two immunizations. Acute replication in the trigeminal ganglia was also prevented in mice immunized twice with wil d-type or mutant virus. The level of protection against infection and disease generated by immunization with replication-defective mutant vi ruses was comparable to that of infectious wild-type virus in all case s. In addition, T-cell proliferative and neutralizing antibody respons es following immunization and corneal challenge were of similar streng th in mice immunized with replication-defective mutant viruses or with wild-type virus. Thus, protein expression by forms of HSV-I capable o f only partially completing the replication cycle can induce an immune response in mice that efficiently decreases primary replication of vi rulent challenge virus, interferes with acute and latent infection of the nervous system, and inhibits the development of both keratitis and systemic neurologic disease.