PMID- 32999018 OWN - NLM STAT- MEDLINE DCOM- 20210125 LR - 20240216 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 94 IP - 24 DP - 2020 Nov 23 TI - Herpes Simplex Virus 1 (HSV-1) 0DeltaNLS Live-Attenuated Vaccine Protects against Ocular HSV-1 Infection in the Absence of Neutralizing Antibody in HSV-1 gB T Cell Receptor-Specific Transgenic Mice. LID - 10.1128/JVI.01000-20 [doi] LID - e01000-20 AB - The contribution of T cell and antibody responses following vaccination in resistance to herpes simplex virus 1 (HSV-1) infection continues to be rigorously investigated. In the present article, we explore the contribution of CD8(+) T cells specific for the major antigenic epitope for HSV-1 glycoprotein B (gB(498-505), gB) in C57BL/6 mice using a transgenic mouse (gBT-I.1) model vaccinated with HSV-1 0DeltaNLS. gBT-I.1-vaccinated mice did not generate a robust neutralization antibody titer in comparison to the HSV-1 0DeltaNLS-vaccinated wild-type C57BL/6 counterpart. Nevertheless, the vaccinated gBT-I.1 mice were resistant to ocular challenge with HSV-1 compared to vehicle-vaccinated animals based on survival and reduced corneal neovascularization but displayed similar levels of corneal opacity. Whereas there was no difference in the virus titer recovered from the cornea comparing vaccinated mice, HSV-1 0DeltaNLS-vaccinated animals possessed significantly less infectious virus during acute infection in the trigeminal ganglia (TG) and brain stem compared to the control-vaccinated group. These results correlated with a significant increase in gB-elicited interferon-gamma (IFN-gamma), granzyme B, and CD107a and a reduction in lymphocyte activation gene 3 (LAG-3), programmed cell death 1 (PD-1), and T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) expressed by TG infiltrating gB-specific CD8(+) T cells from the HSV-1 0DeltaNLS-vaccinated group. Antibody depletion of CD8(+) T cells in HSV-1 0DeltaNLS-vaccinated mice rendered animals highly susceptible to virus-mediated mortality similar to control-vaccinated mice. Collectively, the HSV-1 0DeltaNLS vaccine is effective against ocular HSV-1 challenge, reducing ocular neovascularization and suppressing peripheral nerve virus replication in the near absence of neutralizing antibody in this unique mouse model.IMPORTANCE The role of CD8(+) T cells in antiviral efficacy using a live-attenuated virus as the vaccine is complicated by the humoral immune response. In the case of the herpes simplex virus 1 (HSV-1) 0DeltaNLS vaccine, the correlate of protection has been defined to be primarily antibody driven. The current study shows that in the near absence of anti-HSV-1 antibody, vaccinated mice are protected from subsequent challenge with wild-type HSV-1 as measured by survival. The efficacy is lost following depletion of CD8(+) T cells. Whereas increased survival and reduction in virus replication were observed in vaccinated mice challenged with HSV-1, cornea pathology was mixed with a reduction in neovascularization but no change in opacity. Collectively, the study suggests CD8(+) T cells significantly contribute to the host adaptive immune response to HSV-1 challenge following vaccination with an attenuated virus, but multiple factors are involved in cornea pathology in response to ocular virus challenge. CI - Copyright (c) 2020 American Society for Microbiology. FAU - Gmyrek, Grzegorz B AU - Gmyrek GB AD - Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. FAU - Filiberti, Adrian AU - Filiberti A AD - Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. FAU - Montgomery, Micaela AU - Montgomery M AD - Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. FAU - Chitrakar, Alisha AU - Chitrakar A AD - Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. FAU - Royer, Derek J AU - Royer DJ AD - Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. FAU - Carr, Daniel J J AU - Carr DJJ AUID- ORCID: 0000-0003-1954-2478 AD - Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA Dan-Carr@ouhsc.edu. AD - Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. LA - eng GR - P20 GM103447/GM/NIGMS NIH HHS/United States GR - P30 EY021725/EY/NEI NIH HHS/United States GR - R01 AI053108/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20201123 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Antibodies, Neutralizing) RN - 0 (Antibodies, Viral) RN - 0 (Herpes Simplex Virus Vaccines) RN - 0 (Receptors, Antigen, T-Cell) RN - 0 (Vaccines, Attenuated) RN - 0 (Viral Envelope Proteins) RN - 0 (glycoprotein B, Simplexvirus) SB - IM MH - Animals MH - Antibodies, Neutralizing/*immunology MH - Antibodies, Viral MH - CD8-Positive T-Lymphocytes/immunology MH - Cornea MH - Female MH - Herpes Simplex/immunology/*prevention & control MH - Herpes Simplex Virus Vaccines/*immunology MH - Herpesvirus 1, Human/*immunology MH - Immunization/methods MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Receptors, Antigen, T-Cell/*metabolism MH - Trigeminal Ganglion/metabolism/virology MH - Vaccination MH - Vaccines, Attenuated/*immunology MH - Viral Envelope Proteins/immunology/*metabolism PMC - PMC7925190 OTO - NOTNLM OT - CD8 T cell OT - HSV-1 OT - eye OT - interferon OT - metabolism OT - transgenic mice OT - vaccines EDAT- 2020/10/02 06:00 MHDA- 2021/01/26 06:00 PMCR- 2021/05/23 CRDT- 2020/10/01 05:30 PHST- 2020/05/20 00:00 [received] PHST- 2020/09/21 00:00 [accepted] PHST- 2020/10/02 06:00 [pubmed] PHST- 2021/01/26 06:00 [medline] PHST- 2020/10/01 05:30 [entrez] PHST- 2021/05/23 00:00 [pmc-release] AID - JVI.01000-20 [pii] AID - 01000-20 [pii] AID - 10.1128/JVI.01000-20 [doi] PST - epublish SO - J Virol. 2020 Nov 23;94(24):e01000-20. doi: 10.1128/JVI.01000-20. Print 2020 Nov 23.