HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (Papers in Press[PDF]) All Versions of this Article: vir.0.007336-0v1 90/6/1382    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Barry, G. M. Articles by Fazakerley, J. K. Search for Related Content PubMed PubMed Citation Articles by Barry, G. M. Articles by Fazakerley, J. K. Agricola Articles by Barry, G. M. Articles by Fazakerley, J. K.

PKR acts early in infection to suppress Semliki Forest virus production and strongly enhances the type-I interferon response

University of Edinburgh

¹ E-mail: john.fazakerley{at}ed.ac.uk

The double-stranded (ds) RNA-activated protein kinase (PKR) is a key regulator of protein translation, interferon expression and cell survival. Upon infection of vertebrate cells in continuous culture, the alphavirus Semliki Forest virus (SFV) initiates apoptosis and interferon synthesis. To determine the effect of PKR on SFV infection we studied the course of infection in wt mice and mice with a genetic deletion of PKR (PKR-/-) and mouse embryo fibroblasts (MEFs) derived from these mice. In MEFs, PKR delayed virus protein synthesis, production of infectious virus and caspase-3 activated cell death and reduced the yield of infectious virus by 90%. siRNA suppression of PKR levels in NIH 3T3 cells also reduced virus production and apoptosis. In MEFs, PKR was not required to initiate interferon-β gene transcription but strongly contributed to the magnitude of this response. Levels of interferon-β transcripts in PKR-/- MEFs at 8 h were 80% less than wt and levels of functional interferon at 24 h 95 % lower. Following infection of wt and PKR-/- mice, SFV4 and SFV A7(74) were avirulent. PKR increased levels of serum interferon and the rate of clearance of infectious virus from the brain. In summary in response to SFV, PKR exerts an early anti-viral effect which delays virus protein production and release of infectious virus and, whereas PKR is not required for induction of apoptosis or activation of the type-I interferon response, it strongly augments the type-I interferon response and contributes to clearance of infectious virus from the mouse brain.

Received 15 September 2008; accepted 3 February 2009.