PMID- 25505072
OWN - NLM
STAT- MEDLINE
DCOM- 20150420
LR  - 20210722
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 89
IP  - 5
DP  - 2015 Mar
TI  - Mutations within the pathogenic region of herpes simplex virus 1 gK signal 
      sequences alter cell surface expression and neurovirulence.
PG  - 2530-42
LID - 10.1128/JVI.03506-14 [doi]
AB  - To investigate the role of the signal sequences of herpes simplex virus 1 (HSV-1) 
      gK on virus replication and viral pathogenesis, we constructed recombinant 
      viruses with or without mutations within the signal sequences of gK. These 
      recombinant viruses expressed two additional copies of the mutated (MgK) or 
      native (NgK) form of the gK gene in place of the latency-associated transcript 
      with a myc epitope tag to facilitate detection at their 3' ends. The replication 
      of MgK virus was similar to that of NgK both in vitro and in vivo, as well as in 
      the trigeminal ganglia (TG) of latently infected mice. The levels of gB and gK 
      transcripts in the corneas, TG, and brains of infected mice on days 3 and 5 
      postinfection were markedly virus and time dependent, as well as tissue specific. 
      Mutation in the signal sequence of gK in MgK virus blocked cell surface 
      expression of gK-myc in rabbit skin cells, increased 50% lethal dose, and 
      decreased corneal scarring in ocularly infected mice compared to the NgK or 
      revertant (RgK) virus. MgK and NgK viruses, and not the RgK virus, showed a 
      reduced extent of explant reactivation at the lower dose of ocular infection but 
      not at the higher dose. However, the time of reactivation was not affected by 
      overexpression of the different forms of gK. Taken together, these results 
      strongly suggest that the 8mer peptide (ITAYGLVL) within the signal sequence of 
      gK promotes cell surface expression of gK in infected cells and ocular 
      pathogenesis in infected mice. IMPORTANCE: In this study, we show for the first 
      time that mutations within the signal sequence of gK blocked cell surface 
      expression of inserted recombinant gK in vitro. Furthermore, this blockage in 
      cell surface expression was correlated with higher 50% lethal dose and less 
      corneal scarring in vivo. Thus, these studies point to a key role for the 8mer 
      within the signal sequence of gK in HSV-1-induced pathogenicity.
CI  - Copyright (c) 2015, American Society for Microbiology. All Rights Reserved.
FAU - Matundan, Harry H
AU  - Matundan HH
AD  - Center for Neurobiology and Vaccine Development, Ophthalmology Research, 
      Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
FAU - Mott, Kevin R
AU  - Mott KR
AD  - Center for Neurobiology and Vaccine Development, Ophthalmology Research, 
      Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
FAU - Akhtar, Aslam Abbasi
AU  - Akhtar AA
AD  - Regenerative Medicine Institute and Department of Biomedical Sciences, 
      Cedars-Sinai Medical Center, Los Angeles, California, USA.
FAU - Breunig, Joshua J
AU  - Breunig JJ
AD  - Regenerative Medicine Institute and Department of Biomedical Sciences, 
      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
GR  - R01 EY014966/EY/NEI NIH HHS/United States
GR  - R21 AI093941/AI/NIAID NIH HHS/United States
GR  - 1 R01 EY13615/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20141210
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Membrane Proteins)
RN  - 0 (Protein Sorting Signals)
RN  - 0 (UL53 protein, Human herpesvirus 1)
RN  - 0 (Viral Proteins)
SB  - IM
MH  - Animals
MH  - Brain/virology
MH  - Cells, Cultured
MH  - Cornea/virology
MH  - Disease Models, Animal
MH  - Gene Expression
MH  - Herpes Simplex/pathology/*virology
MH  - Herpesvirus 1, Human/genetics/*growth & development
MH  - Lagomorpha
MH  - Membrane Proteins/genetics/*metabolism
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - *Mutation
MH  - *Protein Sorting Signals
MH  - Time Factors
MH  - Trigeminal Ganglion/virology
MH  - Viral Proteins/genetics/*metabolism
MH  - Virulence
MH  - Virus Replication
PMC - PMC4325753
EDAT- 2014/12/17 06:00
MHDA- 2015/04/22 06:00
PMCR- 2015/09/01
CRDT- 2014/12/16 06:00
PHST- 2014/12/16 06:00 [entrez]
PHST- 2014/12/17 06:00 [pubmed]
PHST- 2015/04/22 06:00 [medline]
PHST- 2015/09/01 00:00 [pmc-release]
AID - JVI.03506-14 [pii]
AID - 03506-14 [pii]
AID - 10.1128/JVI.03506-14 [doi]
PST - ppublish
SO  - J Virol. 2015 Mar;89(5):2530-42. doi: 10.1128/JVI.03506-14. Epub 2014 Dec 10.