Document Detail

Herpes simplex virus dances with amyloid precursor protein while exiting the cell.
MedLine Citation:
PMID:  21483850     Owner:  NLM     Status:  MEDLINE    
Herpes simplex type 1 (HSV1) replicates in epithelial cells and secondarily enters local sensory neuronal processes, traveling retrograde to the neuronal nucleus to enter latency. Upon reawakening newly synthesized viral particles travel anterograde back to the epithelial cells of the lip, causing the recurrent cold sore. HSV1 co-purifies with amyloid precursor protein (APP), a cellular transmembrane glycoprotein and receptor for anterograde transport machinery that when proteolyzed produces A-beta, the major component of senile plaques. Here we focus on transport inside epithelial cells of newly synthesized virus during its transit to the cell surface. We hypothesize that HSV1 recruits cellular APP during transport. We explore this with quantitative immuno-fluorescence, immuno-gold electron-microscopy and live cell confocal imaging. After synchronous infection most nascent VP26-GFP-labeled viral particles in the cytoplasm co-localize with APP (72.8+/-6.7%) and travel together with APP inside living cells (81.1+/-28.9%). This interaction has functional consequences: HSV1 infection decreases the average velocity of APP particles (from 1.1+/-0.2 to 0.3+/-0.1 µm/s) and results in APP mal-distribution in infected cells, while interplay with APP-particles increases the frequency (from 10% to 81% motile) and velocity (from 0.3+/-0.1 to 0.4+/-0.1 µm/s) of VP26-GFP transport. In cells infected with HSV1 lacking the viral Fc receptor, gE, an envelope glycoprotein also involved in viral axonal transport, APP-capsid interactions are preserved while the distribution and dynamics of dual-label particles differ from wild-type by both immuno-fluorescence and live imaging. Knock-down of APP with siRNA eliminates APP staining, confirming specificity. Our results indicate that most intracellular HSV1 particles undergo frequent dynamic interplay with APP in a manner that facilitates viral transport and interferes with normal APP transport and distribution. Such dynamic interactions between APP and HSV1 suggest a mechanistic basis for the observed clinical relationship between HSV1 seropositivity and risk of Alzheimer's disease.
Shi-Bin Cheng; Paulette Ferland; Paul Webster; Elaine L Bearer
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-03-31
Journal Detail:
Title:  PloS one     Volume:  6     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2011  
Date Detail:
Created Date:  2011-04-12     Completed Date:  2011-08-25     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e17966     Citation Subset:  IM    
Department of Pathology and Laboratory Medicine, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
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MeSH Terms
Amyloid beta-Protein Precursor / genetics,  metabolism*
Blotting, Western
Capsid Proteins / genetics,  metabolism
Cell Line
Cercopithecus aethiops
Fluorescent Antibody Technique
Green Fluorescent Proteins / genetics,  metabolism
HeLa Cells
Microscopy, Confocal
Microscopy, Electron
RNA, Small Interfering
Simplexvirus / growth & development*,  physiology*
Vero Cells
Grant Support
Reg. No./Substance:
0/Amyloid beta-Protein Precursor; 0/Capsid Proteins; 0/RNA, Small Interfering; 0/capsid protein VP26, herpes simplex virus type 1; 147336-22-9/Green Fluorescent Proteins

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