title: Disruption of virion host shutoff activity improves the immunogenicity and protective capacity of a replication-incompetent herpes simplex virus type 1 vaccine strain.
abstract: 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.
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Geiss
authors.forename: T J
authors.initials: TJ
authors.lastname: Smith
authors.forename: D A
authors.initials: DA
authors.lastname: Leib
authors.forename: L A
authors.initials: LA
authors.lastname: Morrison
mesh_terms: D000818:Animals; D001835:Body Weight; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins; D005260:Female; D018259:Herpesvirus 1, Human / Q000276:immunology*; D007114:Immunization; D007074:Immunoglobulin G / Q000097:blood; D016849:Keratitis, Herpetic / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D012260:Ribonucleases; D014709:Vero Cells; D014764:Viral Proteins / Q000502:physiology*; D014765:Viral Vaccines / Q000276:immunology*; D014779:Virus Replication
chemical_list: D004268:DNA-Binding Proteins; C045462:ICP8 protein, Simplexvirus; D007074:Immunoglobulin G; D014764:Viral Proteins; D014765:Viral Vaccines; C070722:virion host shutoff protein, Simplexvirus; D012260:Ribonucleases