Multiple Phosphatidylinositol 3-Kinases Regulate Vaccinia Virus Morphogenesis

• Type of Material: Article
• Authors: Shannon McNulty, Emory University; William Bornmann, University of Texas; Jill Schriewer, Saint Louis University Health Sciences Center; Chas Werner, Saint Louis University Health Sciences Center; Scott K. Smith, Centers for Disease Control and Prevention; Victoria A. Olson, Centers for Disease Control and Prevention; Inger K. Damon, Emory University; R. Mark Buller, Saint Louis University Health Sciences Center; John Heuser, Washington University School of Medicine; Daniel Kalman, Emory University
• Language: English
• Date: 2010-05-28
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
• License: Creative Commons Creative Commons CC0 1.0 Universal
• Final Published Version (URL): http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0010884
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 5
• Issue: 5
• Start Page: 1
• End Page: 21
• Grant/Funding Information: This work was supported by National Institutes of Health R56A105896101A2 and R01A107246201A2 to DK.
• Research Categories: Biology, Microbiology; Health Sciences, Immunology

Abstract

Poxvirus morphogenesis is a complex process that involves the successive wrapping of the virus in host cell membranes. We screened by plaque assay a focused library of kinase inhibitors for those that caused a reduction in viral growth and identified several compounds that selectively inhibit phosphatidylinositol 3-kinase (PI3K). Previous studies demonstrated that PI3Ks mediate poxviral entry. Using growth curves and electron microscopy in conjunction with inhibitors, we show that that PI3Ks additionally regulate morphogenesis at two distinct steps: immature to mature virion (IMV) transition, and IMV envelopment to form intracellular enveloped virions (IEV). Cells derived from animals lacking the p85 regulatory subunit of Type I PI3Ks (p85α−/−β−/−) presented phenotypes similar to those observed with PI3K inhibitors. In addition, VV appear to redundantly use PI3Ks, as PI3K inhibitors further reduce plaque size and number in p85α−/−β−/− cells. Together, these data provide evidence for a novel regulatory mechanism for virion morphogenesis involving phosphatidylinositol dynamics and may represent a new therapeutic target to contain poxviruses.