HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein - PubMed (original) (raw)

. 2007 Mar 15;1(1):23-35.

doi: 10.1016/j.chom.2006.12.001.

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HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein

Anthony Orvedahl et al. Cell Host Microbe. 2007.

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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.

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