PMID- 30282707
OWN - NLM
STAT- MEDLINE
DCOM- 20190830
LR  - 20190830
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 92
IP  - 24
DP  - 2018 Dec 15
TI  - Herpes Simplex Virus 1 Latency and the Kinetics of Reactivation Are Regulated by 
      a Complex Network of Interactions between the Herpesvirus Entry Mediator, Its 
      Ligands (gD, BTLA, LIGHT, and CD160), and the Latency-Associated Transcript.
LID - 10.1128/JVI.01451-18 [doi]
LID - e01451-18
AB  - Recently, we reported that the herpesvirus entry mediator (HVEM; also called 
      TNFRSF14 or CD270) is upregulated by the latency-associated transcript (LAT) of 
      herpes simplex virus 1 (HSV-1) and that the absence of HVEM affects latency 
      reactivation but not primary infection in ocularly infected mice. gD has been 
      shown to bind to HVEM. LIGHT (TNFSF14), CD160, and BTLA (B- and T-lymphocyte 
      attenuator) also interact with HVEM and can interfere with HSV gD binding. It was 
      not known if LIGHT, CD160, or BTLA affected the level of latency reactivation in 
      the trigeminal ganglia (TG) of latently infected mice. To address this issue, we 
      ocularly infected LIGHT(-/-), CD160(-/-), and BTLA(-/-) mice with LAT(+) and 
      LAT(-) viruses, using similarly infected wild-type (WT) and HVEM(-/-) mice as 
      controls. The amount of latency, as determined by the levels of gB DNA in the TG 
      of the LIGHT(-/-), CD160(-/-), and BTLA(-/-) mice infected with either LAT(+) or 
      LAT(-) viruses, was lower than that in WT mice infected with LAT(+) virus and was 
      similar in WT mice infected with LAT(-) virus. The levels of LAT RNA in 
      HVEM(-/-), LIGHT(-/-), CD160(-/-), and BTLA(-/-) mice infected with LAT(+) virus 
      were similar and were lower than the levels of LAT RNA in WT mice. However, 
      LIGHT(-/-), CD160(-/-), and BTLA(-/-) mice, independent of the presence of LAT, 
      had levels of reactivation similar to those of WT mice infected with LAT(+) 
      virus. Faster reactivation correlated with the upregulation of HVEM transcript. 
      The LIGHT(-/-), CD160(-/-), and BTLA(-/-) mice had higher levels of HVEM 
      expression, and this, along with the absence of BTLA, LIGHT, or CD160, may 
      contribute to faster reactivation, while the absence of each molecule, 
      independent of LAT, may have contributed to lower latency. This study suggests 
      that, in the absence of competition with gD for binding to HVEM, LAT RNA is 
      important for WT levels of latency but not for WT levels of 
      reactivation.IMPORTANCE The effects of BTLA, LIGHT, and CD160 on latency 
      reactivation are not known. We show here that in BTLA, LIGHT, or CD160 null mice, 
      latency is reduced; however, HVEM expression is upregulated compared to that of 
      WT mice, and this upregulation is associated with higher reactivation that is 
      independent of LAT but dependent on gD expression. Thus, one of the mechanisms by 
      which BTLA, LIGHT, and CD160 null mice enhance reactivation appears to be the 
      increased expression of HVEM in the presence of gD. Thus, our results suggest 
      that blockade of HVEM-LIGHT-BTLA-CD160 contributes to reduced HSV-1 latency and 
      reactivation.
CI  - Copyright (c) 2018 American Society for Microbiology.
FAU - Wang, Shaohui
AU  - Wang S
AD  - Center for Neurobiology and Vaccine Development, Department of Surgery, Cedars 
      Sinai Medical Center, Los Angeles, California, USA.
FAU - Ljubimov, Alexander V
AU  - Ljubimov AV
AD  - Eye Program, Board of Governors Regenerative Medicine Institute, Cedars-Sinai 
      Medical Center and David Geffen School of Medicine, University of California Los 
      Angeles, Los Angeles, California, USA.
FAU - Jin, Ling
AU  - Jin L
AD  - Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State 
      University, Corvallis, Oregon, USA.
FAU - Pfeffer, Klaus
AU  - Pfeffer K
AD  - Institute of Medical Microbiology, University of Dusseldorf, Dusseldorf, Germany.
FAU - Kronenberg, Mitchell
AU  - Kronenberg M
AD  - La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
AD  - University of California-San Diego, La Jolla, California, USA.
FAU - Ghiasi, Homayon
AU  - Ghiasi H
AD  - Center for Neurobiology and Vaccine Development, Department of Surgery, Cedars 
      Sinai Medical Center, Los Angeles, California, USA ghiasih@cshs.org.
LA  - eng
GR  - R01 EY013615/EY/NEI NIH HHS/United States
GR  - R01 EY029160/EY/NEI NIH HHS/United States
GR  - U01 AI125955/AI/NIAID NIH HHS/United States
GR  - P01 DK046763/DK/NIDDK NIH HHS/United States
GR  - R01 EY026944/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20181127
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Antigens, CD)
RN  - 0 (BTLA protein, mouse)
RN  - 0 (Cd160 protein, mouse)
RN  - 0 (GPI-Linked Proteins)
RN  - 0 (MicroRNAs)
RN  - 0 (Receptors, Immunologic)
RN  - 0 (Receptors, Tumor Necrosis Factor, Member 14)
RN  - 0 (Tnfrsf14 protein, mouse)
RN  - 0 (Tnfsf14 protein, mouse)
RN  - 0 (Tumor Necrosis Factor Ligand Superfamily Member 14)
RN  - 0 (Viral Envelope Proteins)
RN  - 0 (glycoprotein D, Human herpesvirus 1)
RN  - 0 (latency associated transcript, herpes simplex virus-1)
SB  - IM
MH  - Animals
MH  - Antigens, CD/*genetics
MH  - Eye Diseases/genetics/*virology
MH  - Female
MH  - GPI-Linked Proteins/genetics
MH  - Gene Knockout Techniques
MH  - Herpes Simplex/*genetics/virology
MH  - Herpesvirus 1, Human/*physiology
MH  - Kinetics
MH  - Male
MH  - Mice
MH  - MicroRNAs/*genetics
MH  - Receptors, Immunologic/*genetics
MH  - Receptors, Tumor Necrosis Factor, Member 14/genetics
MH  - Tumor Necrosis Factor Ligand Superfamily Member 14/*genetics
MH  - Viral Envelope Proteins/genetics
MH  - Virus Internalization
MH  - Virus Latency
MH  - Virus Replication
PMC - PMC6258941
OTO - NOTNLM
OT  - corneal scarring
OT  - eye diseases
OT  - latency
OT  - ocular
OT  - reactivation
OT  - virus replication
EDAT- 2018/10/05 06:00
MHDA- 2019/08/31 06:00
PMCR- 2019/05/27
CRDT- 2018/10/05 06:00
PHST- 2018/08/22 00:00 [received]
PHST- 2018/09/25 00:00 [accepted]
PHST- 2018/10/05 06:00 [pubmed]
PHST- 2019/08/31 06:00 [medline]
PHST- 2018/10/05 06:00 [entrez]
PHST- 2019/05/27 00:00 [pmc-release]
AID - JVI.01451-18 [pii]
AID - JVI01451-18 [pii]
AID - 10.1128/JVI.01451-18 [doi]
PST - epublish
SO  - J Virol. 2018 Nov 27;92(24):e01451-18. doi: 10.1128/JVI.01451-18. Print 2018 Dec 
      15.