PMID- 31511378
OWN - NLM
STAT- MEDLINE
DCOM- 20200615
LR  - 20200615
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 93
IP  - 23
DP  - 2019 Dec 1
TI  - Absence of Signal Peptide Peptidase, an Essential Herpes Simplex Virus 1 
      Glycoprotein K Binding Partner, Reduces Virus Infectivity In Vivo.
LID - 10.1128/JVI.01309-19 [doi]
LID - e01309-19
AB  - We previously reported that herpes simplex virus (HSV) glycoprotein K (gK) binds 
      to signal peptide peptidase (SPP), also known as minor histocompatibility antigen 
      H13. Binding of gK to SPP is required for HSV-1 infectivity in vitro SPP is a 
      member of the gamma-secretase family, and mice lacking SPP are embryonic lethal. To 
      determine how SPP affects HSV-1 infectivity in vivo, the SPP gene was deleted 
      using a tamoxifen-inducible Cre recombinase driven by the ubiquitously expressed 
      ROSA26 promoter. SPP mRNA was reduced by more than 93% in the cornea and 
      trigeminal ganglia (TG) and by 99% in the liver of tamoxifen-injected mice, while 
      SPP protein expression was reduced by 90% compared to the level in control mice. 
      Mice lacking SPP had significantly less HSV-1 replication in the eye as well as 
      reduced gK, UL20, ICP0, and gB transcripts in the cornea and TG compared to 
      levels in control mice. In addition, reduced infiltration of CD45(+), CD4(+), 
      CD8(+), F4/80(+), CD11c(+), and NK1.1(+) T cells was observed in the cornea and 
      TG of SPP-inducible knockout mice compared to that in control mice. Finally, in 
      the absence of SPP, latency was significantly reduced in SPP-inducible knockout 
      mice compared to that in control mice. Thus, in this study we have generated 
      SPP-inducible knockout mice and shown that the absence of SPP affects virus 
      replication in the eye of ocularly infected mice and that this reduction is 
      correlated with the interaction of gK and SPP. These results suggest that 
      blocking this interaction may have therapeutic potential in treating 
      HSV-1-associated eye disease.IMPORTANCE Glycoprotein K (gK) is an essential and 
      highly conserved HSV-1 protein. Previously, we reported that gK binds to SPP, an 
      endoplasmic reticulum (ER) protein, and blocking this binding reduces virus 
      infectivity in vitro and also affects gK and UL20 subcellular localization. To 
      evaluate the function of gK binding to SPP in vivo, we generated SPP-inducible 
      knockout mice and observed the following in the absence of SPP: (i) that 
      significantly less HSV-1 replication was seen in ocularly infected mice than in 
      control mice; (ii) that expression of various HSV-1 genes and cellular 
      infiltrates in the eye and trigeminal ganglia of infected mice was less than that 
      in control mice; and (iii) that latency was significantly reduced in infected 
      mice. Thus, blocking of gK binding to SPP may be a useful tool to control 
      HSV-1-induced eye disease in patients with herpes stromal keratitis (HSK).
CI  - Copyright (c) 2019 American Society for Microbiology.
FAU - Wang, Shaohui
AU  - Wang S
AD  - Center for Neurobiology and Vaccine Development, Ophthalmology Research, 
      Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
FAU - Ghiasi, Homayon
AU  - Ghiasi H
AD  - Center for Neurobiology and Vaccine Development, Ophthalmology Research, 
      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
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20191113
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Immediate-Early Proteins)
RN  - 0 (UL20 protein, Herpes simplex virus type 1)
RN  - 0 (UL53 protein, Human herpesvirus 1)
RN  - 0 (Viral Proteins)
RN  - 094ZI81Y45 (Tamoxifen)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.3.2.27 (Vmw110 protein, Human herpesvirus 1)
RN  - EC 3.4.23.- (Aspartic Acid Endopeptidases)
RN  - EC 3.4.23.- (signal peptide peptidase)
SB  - IM
MH  - Animals
MH  - Aspartic Acid Endopeptidases/drug effects/genetics/*metabolism
MH  - Cell Line
MH  - Cornea/virology
MH  - Disease Models, Animal
MH  - Eye Infections/immunology/virology
MH  - Herpes Simplex/*immunology/virology
MH  - Herpesvirus 1, Human/*physiology
MH  - Immediate-Early Proteins
MH  - Keratitis, Herpetic
MH  - Liver/virology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Tamoxifen/antagonists & inhibitors
MH  - Transcriptome
MH  - Trigeminal Ganglion/virology
MH  - Ubiquitin-Protein Ligases
MH  - Viral Load
MH  - Viral Proteins/*metabolism
MH  - Virus Latency
MH  - Virus Replication
PMC - PMC6854508
OTO - NOTNLM
OT  - HSV-1
OT  - SPP
OT  - inducible knockout
OT  - infiltrates
OT  - ocular infection
OT  - tamoxifen
OT  - viral transcripts
OT  - virus replication
EDAT- 2019/09/13 06:00
MHDA- 2020/06/17 06:00
PMCR- 2020/05/13
CRDT- 2019/09/13 06:00
PHST- 2019/08/06 00:00 [received]
PHST- 2019/09/02 00:00 [accepted]
PHST- 2019/09/13 06:00 [pubmed]
PHST- 2020/06/17 06:00 [medline]
PHST- 2019/09/13 06:00 [entrez]
PHST- 2020/05/13 00:00 [pmc-release]
AID - JVI.01309-19 [pii]
AID - 01309-19 [pii]
AID - 10.1128/JVI.01309-19 [doi]
PST - epublish
SO  - J Virol. 2019 Nov 13;93(23):e01309-19. doi: 10.1128/JVI.01309-19. Print 2019 Dec 
      1.