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

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell host & microbe (Impact Factor: 12.19). 04/2007; 1(1):23-35. DOI: 10.1016/j.chom.2006.12.001
Source: PubMed

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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    • "Subsequent work extended the idea of Beclin 1 as a main regulator of an anti-viral response. Several viruses encode a Beclin 1-binding protein, such as a Herpes Simplex Virus 1 protein, ICP34.5, and viruses lacking this domain are less pathogenic in a mouse encephalitis model (Orvedahl et al., 2007). ICP34.5 binding to Beclin 1 inhibits the formation of autophagosomes in neurons, suggesting that the virus has evolved to actively inhibit autophagy. "
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