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Author Notes:

Corresponding author: Daniel Kalman (Email: dkalman@emory.edu)

Conceived and designed the experiments: SLM, JMS, CAW, SKS, VAO, JEH, and DK.

Performed the experiments: SLM, JMS, CAW, SKS, VAO, and JEH.

Analyzed the data: SLM, JMS, CAW, SKS, VAO, IKD, RMLB, JEH, and DK.

Contributed reagents/materials/analysis tools: SLM and WGB.

Wrote the paper: SLM and DK.

We thank Jay Hooper (USAMRIID), Bernard Moss (NIH) and Stuart Isaacs (University of Pennsylvania) for sharing antibodies and Lewis Cantley (Harvard) for sharing the p85-deficient cells.

Many thanks to Victor Faundez (Emory University) for insightful comments and discussion.

Statistical support was provided by Kirk Easley (Emory University).

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors have declared that no competing interests exist.

Subjects:

Research Funding:

This work was supported by National Institutes of Health R56A105896101A2 and R01A107246201A2 to DK.

Multiple Phosphatidylinositol 3-Kinases Regulate Vaccinia Virus Morphogenesis

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Journal Title:

PLoS ONE

Volume:

Volume 5, Number 5

Publisher:

, Pages 1-21

Type of Work:

Article | Final Publisher PDF

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.

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This is an Open Access article distributed under the terms of the Creative Commons Universal : Public Domain Dedication License ( http://creativecommons.org/publicdomain/zero/1.0/), which permits distribution, public display, and publicly performance, distribution of derivative works, making multiple copies, provided the original work is properly cited.

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