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Journal of Virology, April 2002, p. 3615-3625, Vol. 76, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.8.3615-3625.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Therapeutic Immunization with a Virion Host Shutoff-Defective, Replication-Incompetent Herpes Simplex Virus Type 1 Strain Limits Recurrent Herpetic Ocular Infection

Tammie L. Keadle,1 Lynda A. Morrison,2 Jessica L. Morris,1 Jay S. Pepose,3 and Patrick M. Stuart1*

Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri 63110,1 Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri 63104,2 PeposeVision Institute, Chesterfield, Missouri 630173

Received 4 September 2001/ Accepted 10 January 2002

Immunization of mice with herpes simplex virus type 1 (HSV-1) mutant viruses containing deletions in the gene for virion host shutoff (vhs) protein diminishes primary and recurrent 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, {Delta}41{Delta}29, has combined vhs and replication (ICP8-) deficits and protects BALB/c mice against primary corneal infection equivalent to a vhs- strain (BGS41). Here, we tested the hypothesis that {Delta}41{Delta}29 can protect as well as BGS41 in a therapeutic setting. Because immune response induction varies with the mouse and virus strains studied, we first determined the effect of prophylactic {Delta}41{Delta}29 vaccination on primary ocular infection of NIH inbred mice with HSV-1 McKrae, a model system used to evaluate therapeutic vaccines. In a dose-dependent fashion, prophylactic {Delta}41{Delta}29 vaccination decreased postchallenge tear film virus titers and ocular disease incidence and severity while eliciting high levels of HSV-specific antibodies. Adoptive transfer studies demonstrated a dominant role for immune serum and a lesser role for immune cells in mediating prophylactic protection. Therapeutically, vaccination with {Delta}41{Delta}29 effectively reduced the incidence of UV-B-induced recurrent virus shedding in latently infected mice. Therapeutic {Delta}41{Delta}29 and BGS41 vaccination decreased corneal opacity and delayed-type hypersensitivity responses while elevating antibody titers, compared to controls. These data indicate that replication is not a prerequisite for 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 vaccines.

* Corresponding author. Mailing address: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Box 8096, 660 S. Euclid, St. Louis, MO 63110. Phone: (314) 362-9336. Fax: (314) 362-6985. E-mail: stuart{at}vision.wustl.edu.

Journal of Virology, April 2002, p. 3615-3625, Vol. 76, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.8.3615-3625.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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