Attenuated herpes simplex virus 1 (HSV-1) expressing a mutant form of ICP6 stimulates a strong immune response that protects mice against HSV-1-induced corneal disease

David J. Davido, Eleain M. Tu, Hong Wang, Maria Korom, Andreu Gazquez Casals, P. Jahnu Reddy, Heba Mostafa, Benjamin Combs, Steve D. Haenchen, Lynda A. Morrison

Research output: Contribution to journalArticle

Abstract

We previously isolated a herpes simplex virus 1 (HSV-1) mutant, KOS-NA, that carries two nonsynonymous mutations in UL39, resulting in L393P and R950H amino acid substitutions in infected cell protein 6 (ICP6). Our published data studying KOS-NA pathogenesis strongly suggest that one of these ICP6 substitutions expressed from KOS-NA, R950H, severely impaired acute viral replication in the eyes and trigeminal ganglia of mice after inoculation onto the cornea and consequently impaired establishment and reactivation from latency. Because of its significant neuroattenuation, we tested KOS-NA as a potential prophylactic vaccine against HSV-1 in a mouse model of corneal infection. KOS-NA stimulated stronger antibody and T cell responses than a replication-competent ICP0-null mutant and a replication-incompetent ICP8-null mutant optimized for immunogenicity. Immunizations with the ICP0-, ICP8-, and KOS-NA viruses all reduced replication of wild-type HSV-1 challenge virus in the corneal epithelium to similar extents. Low immunizing doses of KOS-NA and the ICP8- virus, but not the ICP0- virus, protected mice against eyelid disease (blepharitis). Notably, only KOS-NA protected almost completely against corneal disease (keratitis) and greatly reduced latent infection by challenge virus. Thus, vaccination of mice with KOS-NA prior to corneal challenge provides significant protection against HSV-1-mediated disease of the eye, even at a very low immunizing dose. These results suggest that KOS-NA may be the foundation of an effective prophylactic vaccine to prevent or limit HSV-1 ocular diseases.

Original languageEnglish (US)
Article numbere01036-18
JournalJournal of virology
Volume92
Issue number17
DOIs
StatePublished - Sep 1 2018
Externally publishedYes

Fingerprint

corneal diseases
Corneal Diseases
Human herpesvirus 1
Human Herpesvirus 1
immune response
viruses
mutants
mice
Viruses
eye diseases
Eye Diseases
Proteins
proteins
eyelid diseases
Eyelid Diseases
cells
Vaccines
vaccination
Blepharitis
vaccines

Keywords

  • Cornea
  • Herpes simplex virus
  • HSV-1
  • ICP6
  • Immunization
  • Keratitis
  • Mutant
  • Ocular
  • Vaccine

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Attenuated herpes simplex virus 1 (HSV-1) expressing a mutant form of ICP6 stimulates a strong immune response that protects mice against HSV-1-induced corneal disease. / Davido, David J.; Tu, Eleain M.; Wang, Hong; Korom, Maria; Casals, Andreu Gazquez; Jahnu Reddy, P.; Mostafa, Heba; Combs, Benjamin; Haenchen, Steve D.; Morrison, Lynda A.

In: Journal of virology, Vol. 92, No. 17, e01036-18, 01.09.2018.

Research output: Contribution to journalArticle

Davido, David J. ; Tu, Eleain M. ; Wang, Hong ; Korom, Maria ; Casals, Andreu Gazquez ; Jahnu Reddy, P. ; Mostafa, Heba ; Combs, Benjamin ; Haenchen, Steve D. ; Morrison, Lynda A. / Attenuated herpes simplex virus 1 (HSV-1) expressing a mutant form of ICP6 stimulates a strong immune response that protects mice against HSV-1-induced corneal disease. In: Journal of virology. 2018 ; Vol. 92, No. 17.
@article{d829a0967ef64c3da9cc478ebcf3ccb3,
title = "Attenuated herpes simplex virus 1 (HSV-1) expressing a mutant form of ICP6 stimulates a strong immune response that protects mice against HSV-1-induced corneal disease",
abstract = "We previously isolated a herpes simplex virus 1 (HSV-1) mutant, KOS-NA, that carries two nonsynonymous mutations in UL39, resulting in L393P and R950H amino acid substitutions in infected cell protein 6 (ICP6). Our published data studying KOS-NA pathogenesis strongly suggest that one of these ICP6 substitutions expressed from KOS-NA, R950H, severely impaired acute viral replication in the eyes and trigeminal ganglia of mice after inoculation onto the cornea and consequently impaired establishment and reactivation from latency. Because of its significant neuroattenuation, we tested KOS-NA as a potential prophylactic vaccine against HSV-1 in a mouse model of corneal infection. KOS-NA stimulated stronger antibody and T cell responses than a replication-competent ICP0-null mutant and a replication-incompetent ICP8-null mutant optimized for immunogenicity. Immunizations with the ICP0-, ICP8-, and KOS-NA viruses all reduced replication of wild-type HSV-1 challenge virus in the corneal epithelium to similar extents. Low immunizing doses of KOS-NA and the ICP8- virus, but not the ICP0- virus, protected mice against eyelid disease (blepharitis). Notably, only KOS-NA protected almost completely against corneal disease (keratitis) and greatly reduced latent infection by challenge virus. Thus, vaccination of mice with KOS-NA prior to corneal challenge provides significant protection against HSV-1-mediated disease of the eye, even at a very low immunizing dose. These results suggest that KOS-NA may be the foundation of an effective prophylactic vaccine to prevent or limit HSV-1 ocular diseases.",
keywords = "Cornea, Herpes simplex virus, HSV-1, ICP6, Immunization, Keratitis, Mutant, Ocular, Vaccine",
author = "Davido, {David J.} and Tu, {Eleain M.} and Hong Wang and Maria Korom and Casals, {Andreu Gazquez} and {Jahnu Reddy}, P. and Heba Mostafa and Benjamin Combs and Haenchen, {Steve D.} and Morrison, {Lynda A.}",
year = "2018",
month = "9",
day = "1",
doi = "10.1128/JVI.01036-18",
language = "English (US)",
volume = "92",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "17",

}

TY - JOUR

T1 - Attenuated herpes simplex virus 1 (HSV-1) expressing a mutant form of ICP6 stimulates a strong immune response that protects mice against HSV-1-induced corneal disease

AU - Davido, David J.

AU - Tu, Eleain M.

AU - Wang, Hong

AU - Korom, Maria

AU - Casals, Andreu Gazquez

AU - Jahnu Reddy, P.

AU - Mostafa, Heba

AU - Combs, Benjamin

AU - Haenchen, Steve D.

AU - Morrison, Lynda A.

PY - 2018/9/1

Y1 - 2018/9/1

N2 - We previously isolated a herpes simplex virus 1 (HSV-1) mutant, KOS-NA, that carries two nonsynonymous mutations in UL39, resulting in L393P and R950H amino acid substitutions in infected cell protein 6 (ICP6). Our published data studying KOS-NA pathogenesis strongly suggest that one of these ICP6 substitutions expressed from KOS-NA, R950H, severely impaired acute viral replication in the eyes and trigeminal ganglia of mice after inoculation onto the cornea and consequently impaired establishment and reactivation from latency. Because of its significant neuroattenuation, we tested KOS-NA as a potential prophylactic vaccine against HSV-1 in a mouse model of corneal infection. KOS-NA stimulated stronger antibody and T cell responses than a replication-competent ICP0-null mutant and a replication-incompetent ICP8-null mutant optimized for immunogenicity. Immunizations with the ICP0-, ICP8-, and KOS-NA viruses all reduced replication of wild-type HSV-1 challenge virus in the corneal epithelium to similar extents. Low immunizing doses of KOS-NA and the ICP8- virus, but not the ICP0- virus, protected mice against eyelid disease (blepharitis). Notably, only KOS-NA protected almost completely against corneal disease (keratitis) and greatly reduced latent infection by challenge virus. Thus, vaccination of mice with KOS-NA prior to corneal challenge provides significant protection against HSV-1-mediated disease of the eye, even at a very low immunizing dose. These results suggest that KOS-NA may be the foundation of an effective prophylactic vaccine to prevent or limit HSV-1 ocular diseases.

AB - We previously isolated a herpes simplex virus 1 (HSV-1) mutant, KOS-NA, that carries two nonsynonymous mutations in UL39, resulting in L393P and R950H amino acid substitutions in infected cell protein 6 (ICP6). Our published data studying KOS-NA pathogenesis strongly suggest that one of these ICP6 substitutions expressed from KOS-NA, R950H, severely impaired acute viral replication in the eyes and trigeminal ganglia of mice after inoculation onto the cornea and consequently impaired establishment and reactivation from latency. Because of its significant neuroattenuation, we tested KOS-NA as a potential prophylactic vaccine against HSV-1 in a mouse model of corneal infection. KOS-NA stimulated stronger antibody and T cell responses than a replication-competent ICP0-null mutant and a replication-incompetent ICP8-null mutant optimized for immunogenicity. Immunizations with the ICP0-, ICP8-, and KOS-NA viruses all reduced replication of wild-type HSV-1 challenge virus in the corneal epithelium to similar extents. Low immunizing doses of KOS-NA and the ICP8- virus, but not the ICP0- virus, protected mice against eyelid disease (blepharitis). Notably, only KOS-NA protected almost completely against corneal disease (keratitis) and greatly reduced latent infection by challenge virus. Thus, vaccination of mice with KOS-NA prior to corneal challenge provides significant protection against HSV-1-mediated disease of the eye, even at a very low immunizing dose. These results suggest that KOS-NA may be the foundation of an effective prophylactic vaccine to prevent or limit HSV-1 ocular diseases.

KW - Cornea

KW - Herpes simplex virus

KW - HSV-1

KW - ICP6

KW - Immunization

KW - Keratitis

KW - Mutant

KW - Ocular

KW - Vaccine

UR - http://www.scopus.com/inward/record.url?scp=85051754529&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85051754529&partnerID=8YFLogxK

U2 - 10.1128/JVI.01036-18

DO - 10.1128/JVI.01036-18

M3 - Article

C2 - 29950407

AN - SCOPUS:85051754529

VL - 92

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 17

M1 - e01036-18

ER -