HSV-1 ICP34.5 Confers Neurovirulence by Targeting the Beclin 1 Autophagy Protein

Anthony Orvedahl, Diane Alexander, Zsolt Tallóczy, Qihua Sun, Yongjie Wei, Wei Zhang, Dennis Burns, David A. Leib, Beth Levine

Research output: Contribution to journalArticle

537 Scopus citations

Abstract

Autophagy is postulated to play a role in antiviral innate immunity. However, it is unknown whether viral evasion of autophagy is important in disease pathogenesis. Here we show that the herpes simplex virus type 1 (HSV-1)-encoded neurovirulence protein ICP34.5 binds to the mammalian autophagy protein Beclin 1 and inhibits its autophagy function. A mutant HSV-1 virus lacking the Beclin 1-binding domain of ICP34.5 fails to inhibit autophagy in neurons and demonstrates impaired ability to cause lethal encephalitis in mice. The neurovirulence of this Beclin 1-binding mutant virus is restored in pkr-/- mice. Thus, ICP34.5-mediated antagonism of the autophagy function of Beclin 1 is essential for viral neurovirulence, and the antiviral signaling molecule PKR lies genetically upstream of Beclin 1 in host defense against HSV-1. Our findings suggest that autophagy inhibition is a novel molecular mechanism by which viruses evade innate immunity and cause fatal disease.

Original languageEnglish (US)
Pages (from-to)23-35
Number of pages13
JournalCell Host and Microbe
Volume1
Issue number1
DOIs
StatePublished - Mar 15 2007

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Keywords

  • MICROBIO

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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