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Journal of Virology, June 2009, p. 5466-5476, Vol. 83, No. 11
0022-538X/09/$08.00+0     doi:10.1128/JVI.02670-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Varicella-Zoster Virus Infection Induces Autophagy in both Cultured Cells and Human Skin Vesicles{triangledown}

Marie-Noëlle Takahashi,1 Wallen Jackson,3 Donna T. Laird,1 Timothy D. Culp,2 Charles Grose,3 John I. Haynes II,1* and Luca Benetti1*

Global Vaccines Technology and Engineering-Bioanalytics, Merck Manufacturing Division,1 Bioprocess Analytical and Formulation Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, Pennsylvania 19486,2 University of Iowa College of Medicine, Iowa City, Iowa 522423

Received 29 December 2008/ Accepted 12 March 2009

When grown in cultured cells, varicella-zoster virus (VZV) forms many aberrant light particles and produces low titers. Various studies have explored the reasons for such a phenotype and have pointed to impaired expression of specific late genes and at lysosomal targeting of egressing virions as possible causes. In the studies presented here, we report that the autophagic degradation pathway was induced at late time points after VZV infection of cultured cells, as documented by immunoblot analysis of the cellular proteins LC3B and p62/SQSTM1, along with electron microscopy analysis, which demonstrated the presence of both early autophagosomes and late autophagic compartments. Autophagy was induced in infected cells even in the presence of phosphonoacetic acid, an inhibitor of viral late gene expression, thus suggesting that accumulation of immediate-early and early viral gene products might be the major stimulus for its induction. We also showed that the autophagic response was not dependent on a specific cell substrate, virus strain, or type of inoculum. Finally, using immunofluorescence imaging, we demonstrated autophagosome-specific staining in human zoster vesicles but not in normal skin. Thus, our results document that this innate immune response pathway is a component of the VZV infectious cycle in both cultured cells and the human skin vesicle, the final site of virion formation in the infected human host.

* Corresponding author. Mailing address: Merck & Co., Inc., WP17-101, 770 Sumneytown Pike, P.O. Box 4, West Point, PA 19486. Phone for John I. Haynes II: (215) 652-2671. Phone for Luca Benetti: (215) 652-9758. Fax: (215) 993-4851. E-mail for John I. Haynes II: john_haynes{at}merck.com. E-mail for Luca Benetti: luca_benetti{at}merck.com

{triangledown} Published ahead of print on 18 March 2009.

Journal of Virology, June 2009, p. 5466-5476, Vol. 83, No. 11
0022-538X/09/$08.00+0     doi:10.1128/JVI.02670-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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