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Journal of Virology, December 2000, p. 11137-11144, Vol. 74, No. 23
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Disruption of Virion Host Shutoff Activity Improves the Immunogenicity and Protective Capacity of a Replication-Incompetent Herpes Simplex Virus Type 1 Vaccine Strain

Brian J. Geiss,1 Tracy J. Smith,2 David A. Leib,2,3 and Lynda A. Morrison1,*

Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri 63104,1 and Departments of Ophthalmology and Visual Sciences2 and Molecular Microbiology,3 Washington University School of Medicine, St. Louis, Missouri 63110

Received 21 June 2000/Accepted 31 August 2000

The virion host shutoff (vhs) protein encoded by herpes simplex virus type 1 (HSV-1) destabilizes both viral and host mRNAs. An HSV-1 strain with a mutation in vhs is attenuated in virulence and induces immune responses in mice that are protective against corneal infection with virulent HSV-1, but it has the capacity to establish latency. Similarly, a replication-incompetent HSV-1 strain with a mutation in ICP8 elicits an immune response protective against corneal challenge, but it may be limited in viral antigen production. We hypothesized therefore that inactivation of vhs in an ICP8- virus would yield a replication-incompetent mutant with enhanced immunogenicity and protective capacity. In this study, a vhs-/ICP8- HSV-1 mutant was engineered. BALB/c mice were immunized with incremental doses of the vhs-/ICP8- double mutant or vhs- or ICP8- single mutants, or the mice were mock immunized, and protective immunity against corneal challenge with virulent HSV-1 was assessed. Mice immunized with the vhs-/ICP8- mutant showed prechallenge serum immunoglobulin G titers comparable to those immunized with replication-competent vhs- virus and exceed those of mice immunized with the ICP8- single mutant. Following corneal challenge, the degrees of protection against ocular disease, weight loss, encephalitis, and establishment of latency were similar for vhs-/ICP8- and vhs- virus-vaccinated mice. Moreover, the double deleted vhs-/ICP8- virus protected mice better in all respects than the single deleted ICP8- mutant virus. The data indicate that inactivation of vhs in a replication-incompetent virus significantly enhances its protective efficacy while retaining its safety for potential human vaccination. Possible mechanisms of enhanced immunogenicity are discussed.

* Corresponding author. Mailing address: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1402 S. Grand Blvd., St. Louis, MO 63104. Phone: (314) 577-8321. Fax: (314) 773-3403. E-mail: morrisla{at}slu.edu.

Journal of Virology, December 2000, p. 11137-11144, Vol. 74, No. 23
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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