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Journal of Virology, November 2009, p. 11665-11672, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01092-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Akt Inhibitor Akt-IV Blocks Virus Replication through an Akt-Independent Mechanism{triangledown}

Ewan F. Dunn, Rachel Fearns, and John H. Connor*

Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts 02118

Received 28 May 2009/ Accepted 31 August 2009

Many viruses activate the phosphatidylinositol 3'-kinase (PI3k)/Akt intracellular signaling pathway to promote viral replication. We have analyzed whether a rapidly replicating rhabdovirus, vesicular stomatitis virus (VSV), requires the PI3k/Akt signaling pathway for its replication. Through the use of chemical inhibitors of PI3k and Akt, we show that VSV replication and cytopathic effects do not require activation of these kinases. Inhibitors that block the activating phosphorylations of Akt at threonine 308 (Thr308) and serine 473 (Ser473) did not inhibit VSV protein expression or the induction of the cytopathic effects of VSV. One compound, Akt inhibitor Akt-IV, inhibited the replication of VSV, respiratory syncytial virus, and vaccinia virus but increased the phosphorylation of Akt at positions Thr308 and Ser473 and did not inhibit Akt kinase activity in vitro. Together, our data suggest that the PI3k/Akt pathway is of limited relevance to the replication of VSV but that Akt inhibitor Akt-IV is a novel broad-spectrum antiviral compound with a mechanism differing from that of its previously reported effect on the PI3k/Akt pathway. Identification of other targets for this compound may define a new approach for blocking virus replication.

* Corresponding author. Mailing address: Department of Microbiology, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118. Phone: (617) 638-0339. Fax: (617) 638-4286. E-mail: jhconnor{at}bu.edu

{triangledown} Published ahead of print on 9 September 2009.

Journal of Virology, November 2009, p. 11665-11672, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01092-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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