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TL Keadle, LA Morrison, JL Morris, JS Pepose, PM Stuart; Therapeutic Immunization with a Virion Host Shutoff (vhs) Defective, Replication-Incompetent HSV-1 Strain Limits Recurrent Herpetic Ocular Infection . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3854.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:Immunization of mice with herpes simplex virus 1 (HSV-1) mutant viruses containing deletions in the virion host shutoff (vhs) gene induces protection against recurrent as well as primary corneal infection with wild type HSV-1. Vhs mutant viruses are severely attenuated in vivo, but establish latent infections in sensory neurons. A safer HSV-1 mutant vaccine strain, Δ;41/Δ;29, has combined vhs and replication (ICP8-) deficits, and provides protection to BALB/c mice against primary corneal infection equivalent to that of a vhs- strain (BGS41). Here, we tested the hypothesis that Δ;41/Δ;29 can protect as well as BGS41 in a therapeutic setting. Methods:Because immune response induction may vary with the mouse and virus strains studied, we first determined the effect of prophylactic Δ;41/Δ;29 vaccination on primary ocular infection of NIH inbred mice with HSV-1 McKrae-the same mouse/virus combination to be used in evaluating therapeutic vaccines. Accordingly, in prophylactic studies, mice were vaccinated with Δ;41/Δ;29 4 weeks prior to corneal challenge infection with HSV. In therapeutic studies, mice with latent ocular HSV infection were vaccinated with BGS41 or Δ;41/Δ;29 4 months after primary infection, and viral reactivation was induced by UV-B light 4 weeks later. Results:In a dose dependent fashion, prophylactic Δ;41/Δ;29 vaccination decreased post challenge tear film virus titers and ocular disease incidence and severity, while eliciting high levels of HSV-specific antibodies. Therapeutically, immunization with Δ;41/Δ;29 effectively reduced the incidence of UV-B-induced recurrent virus shedding in latently infected mice. Therapeutic Δ;41/Δ;29 and BGS41 immunization decreased corneal opacity while elevating antibody titers compared to control vaccine. Immunopathologic delayed type hypersensitivity responses were decreased in both vaccine groups. Conclusion: These data indicate that replication is not a prerequisite for the generation of therapeutic immunity by live HSV mutant virus vaccines, and raise the possibility that genetically tailored replication-defective viruses may make effective and safe therapeutic vaccine candidates.
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