PMID- 31217250
OWN - NLM
STAT- MEDLINE
DCOM- 20200707
LR  - 20221207
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 93
IP  - 18
DP  - 2019 Sep 15
TI  - Blockade of PD-1 and LAG-3 Immune Checkpoints Combined with Vaccination Restores 
      the Function of Antiviral Tissue-Resident CD8(+) T(RM) Cells and Reduces Ocular 
      Herpes Simplex Infection and Disease in HLA Transgenic Rabbits.
LID - 10.1128/JVI.00827-19 [doi]
LID - e00827-19
AB  - Chronic viruses such as herpes simplex virus 1 (HSV-1) evade the hosts' immune 
      system by inducing the exhaustion of antiviral T cells. In the present study, we 
      found that exhausted HSV-specific CD8(+) T cells, with elevated expression of 
      programmed death ligand-1 (PD-1) and lymphocyte activation gene-3 (LAG-3) 
      receptors were frequent in symptomatic patients, with a history of numerous 
      episodes of recurrent corneal herpetic disease, compared to asymptomatic patients 
      who never had corneal herpetic disease. Subsequently, using a rabbit model of 
      recurrent ocular herpes, we found that the combined blockade of PD-1 and LAG-3 
      pathways with antagonist antibodies significantly restored the function of 
      tissue-resident antiviral CD8(+) T(RM) cells in both the cornea and the 
      trigeminal ganglia (TG). An increased number of functional tissue-resident 
      HSV-specific CD8(+) T(RM) cells in latently infected rabbits was associated with 
      protection against recurrent herpes infection and disease. Compared to the PD-1 
      or LAG-3 blockade alone, the combined blockade of PD-1 and LAG-3 appeared to have 
      a synergistic effect in generating frequent polyfunctional Ki-67(+), IFN-gamma(+), 
      CD107(+), and CD8(+) T cells. Moreover, using the human leukocyte antigen (HLA) 
      transgenic rabbit model, we found that dual blockade of PD-1 and LAG-3 reinforced 
      the effect of a multiepitope vaccine in boosting the frequency of HSV-1-specific 
      CD8(+) T(RM) cells and reducing disease severity. Thus, both the PD-1 and the 
      LAG-3 exhaustion pathways play a fundamental role in ocular herpes T cell 
      immunopathology and provide important immune checkpoint targets to combat ocular 
      herpes.IMPORTANCE HSV-specific tissue-resident memory CD8(+) T(RM) cells play a 
      critical role in preventing virus reactivation from latently infected TG and 
      subsequent virus shedding in tears that trigger the recurrent corneal herpetic 
      disease. In this report, we determined how the dual blockade of PD-1 and LAG-3 
      immune checkpoints, combined with vaccination, improved the function of CD8(+) 
      T(RM) cells associated with a significant reduction in recurrent ocular herpes in 
      HLA transgenic (Tg) rabbit model. The combined blockade of PD-1 and LAG-3 
      appeared to have a synergistic effect in generating frequent polyfunctional 
      CD8(+) T(RM) cells that infiltrated both the cornea and the TG. The preclinical 
      findings using the established HLA Tg rabbit model of recurrent herpes highlight 
      that blocking immune checkpoints combined with a T cell-based vaccine would 
      provide an important strategy to combat recurrent ocular herpes in the clinic.
CI  - Copyright (c) 2019 American Society for Microbiology.
FAU - Roy, Soumyabrata
AU  - Roy S
AD  - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, 
      School of Medicine, University of California-Irvine, Irvine, California, USA.
FAU - Coulon, Pierre-Gregoire
AU  - Coulon PG
AD  - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, 
      School of Medicine, University of California-Irvine, Irvine, California, USA.
FAU - Prakash, Swayam
AU  - Prakash S
AD  - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, 
      School of Medicine, University of California-Irvine, Irvine, California, USA.
FAU - Srivastava, Ruchi
AU  - Srivastava R
AD  - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, 
      School of Medicine, University of California-Irvine, Irvine, California, USA.
FAU - Geertsema, Roger
AU  - Geertsema R
AD  - University Laboratory Animal Resources, University of California-Irvine, Irvine, 
      California, USA.
FAU - Dhanushkodi, Nisha
AU  - Dhanushkodi N
AD  - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, 
      School of Medicine, University of California-Irvine, Irvine, California, USA.
FAU - Lam, Cynthia
AU  - Lam C
AD  - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, 
      School of Medicine, University of California-Irvine, Irvine, California, USA.
FAU - Nguyen, Vivianna
AU  - Nguyen V
AD  - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, 
      School of Medicine, University of California-Irvine, Irvine, California, USA.
FAU - Gorospe, Elyssa
AU  - Gorospe E
AD  - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, 
      School of Medicine, University of California-Irvine, Irvine, California, USA.
FAU - Nguyen, Angela M
AU  - Nguyen AM
AD  - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, 
      School of Medicine, University of California-Irvine, Irvine, California, USA.
FAU - Salazar, Stephanie
AU  - Salazar S
AD  - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, 
      School of Medicine, University of California-Irvine, Irvine, California, USA.
FAU - Alomari, Nuha I
AU  - Alomari NI
AD  - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, 
      School of Medicine, University of California-Irvine, Irvine, California, USA.
FAU - Warsi, Wasay R
AU  - Warsi WR
AD  - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, 
      School of Medicine, University of California-Irvine, Irvine, California, USA.
FAU - BenMohamed, Lbachir
AU  - BenMohamed L
AD  - Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, 
      School of Medicine, University of California-Irvine, Irvine, California, USA 
      Lbenmoha@uci.edu.
AD  - Department of Molecular Biology and Biochemistry, School of Medicine, University 
      of California-Irvine, Irvine, California, USA.
AD  - Institute for Immunology, School of Medicine, University of California-Irvine, 
      Irvine, California, USA.
LA  - eng
GR  - R41 AI138764/AI/NIAID NIH HHS/United States
GR  - R01 EY026103/EY/NEI NIH HHS/United States
GR  - R01 AI143348/AI/NIAID NIH HHS/United States
GR  - R01 AI158060/AI/NIAID NIH HHS/United States
GR  - R01 EY019896/EY/NEI NIH HHS/United States
GR  - R01 AI150091/AI/NIAID NIH HHS/United States
GR  - R21 AI143326/AI/NIAID NIH HHS/United States
GR  - R01 EY024618/EY/NEI NIH HHS/United States
GR  - R21 AI110902/AI/NIAID NIH HHS/United States
GR  - R21 AI147499/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 - 20190828
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Antigens, CD)
RN  - 0 (B7-H1 Antigen)
RN  - 0 (CD274 protein, human)
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (HLA Antigens)
RN  - 0 (HLA-A2 Antigen)
RN  - 0 (Herpes Simplex Virus Vaccines)
RN  - 0 (Histocompatibility Antigens)
RN  - 0 (Histocompatibility Antigens Class II)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - 0 (Lymphocyte Activation Gene 3 Protein)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Antigens, CD/*immunology/metabolism
MH  - B7-H1 Antigen/metabolism
MH  - CD8-Positive T-Lymphocytes/immunology
MH  - Cornea/virology
MH  - Epitopes, T-Lymphocyte/immunology
MH  - Female
MH  - HLA Antigens/metabolism
MH  - HLA-A2 Antigen/immunology
MH  - Herpes Simplex Virus Vaccines/immunology
MH  - Herpesvirus 1, Human/immunology/*metabolism
MH  - Histocompatibility Antigens/metabolism
MH  - Histocompatibility Antigens Class II/metabolism
MH  - Humans
MH  - Immunization/methods
MH  - Male
MH  - Middle Aged
MH  - Programmed Cell Death 1 Receptor/*immunology/metabolism
MH  - Rabbits
MH  - Trigeminal Ganglion/virology
MH  - Vaccination/methods
MH  - Virus Shedding/immunology/physiology
MH  - Lymphocyte Activation Gene 3 Protein
PMC - PMC6714801
OTO - NOTNLM
OT  - CD8+ T cell
OT  - HSV-1
OT  - LAG-3
OT  - PD-1
OT  - disease
OT  - herpes
OT  - ocular
OT  - protection
OT  - rabbit
OT  - vaccine
EDAT- 2019/06/21 06:00
MHDA- 2020/07/08 06:00
PMCR- 2020/02/28
CRDT- 2019/06/21 06:00
PHST- 2019/05/16 00:00 [received]
PHST- 2019/06/14 00:00 [accepted]
PHST- 2019/06/21 06:00 [pubmed]
PHST- 2020/07/08 06:00 [medline]
PHST- 2019/06/21 06:00 [entrez]
PHST- 2020/02/28 00:00 [pmc-release]
AID - JVI.00827-19 [pii]
AID - 00827-19 [pii]
AID - 10.1128/JVI.00827-19 [doi]
PST - epublish
SO  - J Virol. 2019 Aug 28;93(18):e00827-19. doi: 10.1128/JVI.00827-19. Print 2019 Sep 
      15.