Document Detail


Mutagenesis of varicella-zoster virus glycoprotein I (gI) identifies a cysteine residue critical for gE/gI heterodimer formation, gI structure, and virulence in skin cells.
MedLine Citation:
PMID:  21345964     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Varicella-zoster virus (VZV) is the alphaherpesvirus that causes chicken pox (varicella) and shingles (zoster). The two VZV glycoproteins gE and gI form a heterodimer that mediates efficient cell-to-cell spread. Deletion of gI yields a small-plaque-phenotype virus, ΔgI virus, which is avirulent in human skin using the xenograft model of VZV pathogenesis. In the present study, 10 mutant viruses were generated to determine which residues were required for the typical function of gI. Three phosphorylation sites in the cytoplasmic domain of gI were not required for VZV virulence in vivo. Two deletion mutants mapped a gE binding region in gI to residues 105 to 125. A glycosylation site, N116, in this region did not affect virulence. Substitution of four cysteine residues highly conserved in the Alphaherpesvirinae established that C95 is required for gE/gI heterodimer formation. The C95A and Δ105-125 (with residues 105 to 125 deleted) viruses had small-plaque phenotypes with reduced replication kinetics in vitro similar to those of the ΔgI virus. The Δ105-125 virus was avirulent for human skin in vivo. In contrast, the C95A mutant replicated in vivo but with significantly reduced kinetics compared to those of the wild-type virus. In addition to abolished gE/gI heterodimer formation, gI from the C95A or the Δ105-125 mutant was not recognized by monoclonal antibodies that detect the canonical conformation of gI, demonstrating structural disruption of gI in these viruses. This alteration prevented gI incorporation into virus particles. Thus, residues C95 and 105 to 125 are critical for gI structure required for gE/gI heterodimer formation, virion incorporation, and ultimately, effective viral spread in human skin.
Authors:
Stefan L Oliver; Marvin H Sommer; Mike Reichelt; Jaya Rajamani; Leonssia Vlaycheva-Beisheim; Shaye Stamatis; Jason Cheng; Carol Jones; James Zehnder; Ann M Arvin
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-02-23
Journal Detail:
Title:  Journal of virology     Volume:  85     ISSN:  1098-5514     ISO Abbreviation:  J. Virol.     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-04-18     Completed Date:  2011-06-14     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  0113724     Medline TA:  J Virol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4095-110     Citation Subset:  IM    
Affiliation:
Stanford University School of Medicine, Stanford, CA 94305, USA. sloliver@stanford.edu
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Substitution
Cell Line
Cysteine / genetics
DNA Mutational Analysis
Herpesvirus 3, Human / genetics,  pathogenicity*
Humans
Protein Interaction Mapping*
Protein Multimerization*
Sequence Deletion
Skin / pathology,  virology*
Viral Envelope Proteins / genetics,  metabolism*
Viral Plaque Assay
Virulence
Virulence Factors / genetics,  metabolism*
Virus Replication
Grant Support
ID/Acronym/Agency:
AI053846/AI/NIAID NIH HHS; AI20459/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Viral Envelope Proteins; 0/Virulence Factors; 0/glycoprotein gp1, varicella-zoster virus; 52-90-4/Cysteine
Comments/Corrections

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