title: Impact of Type I Interferon on the Safety and Immunogenicity of an Experimental Live-Attenuated Herpes Simplex Virus 1 Vaccine in Mice.
abstract: Viral fitness dictates virulence and capacity to evade host immune defenses. Understanding the biological underpinnings of such features is essential for rational vaccine development. We have previously shown that the live-attenuated herpes simplex virus 1 (HSV-1) mutant lacking the nuclear localization signal (NLS) on the ICP0 gene (0ΔNLS) is sensitive to inhibition by interferon beta (IFN-β)in vitroand functions as a highly efficacious experimental vaccine. Here, we characterize the host immune response andin vivopathogenesis of HSV-1 0ΔNLS relative to its fully virulent parental strain in C57BL/6 mice. Additionally, we explore the role of type 1 interferon (IFN-α/β) signaling on virulence and immunogenicity of HSV-1 0ΔNLS and uncover a probable sex bias in the induction of IFN-α/β in the cornea during HSV-1 infection. Our data show that HSV-1 0ΔNLS lacks neurovirulence even in highly immunocompromised mice lacking the IFN-α/β receptor. These studies support the translational viability of the HSV-1 0ΔNLS vaccine strain by demonstrating that, while it is comparable to a virulent parental strain in terms of immunogenicity, HSV-1 0ΔNLS does not induce significant tissue pathology.IMPORTANCEHSV-1 is a common human pathogen associated with a variety of clinical presentations ranging in severity from periodic "cold sores" to lethal encephalitis. Despite the consistent failures of HSV subunit vaccines in clinical trials spanning the past 28 years, opposition to live-attenuated HSV vaccines predicated on unfounded safety concerns currently limits their widespread acceptance. Here, we demonstrate that a live-attenuated HSV-1 vaccine has great translational potential.
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Royer
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Meghan M
authors.initials: MM
authors.lastname: Carr
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Ana J
authors.initials: AJ
authors.lastname: Chucair-Elliott
authors.affiliation: Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Halford
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA Carr@ouhsc.edu.|Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Daniel J J
authors.initials: DJJ
authors.lastname: Carr
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D003315:Cornea / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D006561:Herpes Simplex / Q000517:prevention & control*; D022301:Herpes Simplex Virus Vaccines / Q000008:administration & dosage / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000276:immunology*; D007370:Interferon Type I / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000276:immunology
chemical_list: D022301:Herpes Simplex Virus Vaccines; D007370:Interferon Type I; D014613:Vaccines, Attenuated
keywords: HSV-1; T cells; antibody; cornea; mouse; neovascularization