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Journal of Virology, March 2009, p. 2406-2416, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.01972-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

E4orf1 Limits the Oncolytic Potential of the E1B-55K Deletion Mutant Adenovirus{triangledown}

Michael A. Thomas,1 Robin S. Broughton,2 Felicia D. Goodrum,3 and David A. Ornelles1,4*

Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina,1 Center for AIDS Health Disparities Research, School of Medicine, Meharry Medical College,; Nashville, Tennessee,2 Department of Immunobiology and BIO5 Institute, University of Arizona, Tucson, Arizona,3 Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, North Carolina4

Received 18 September 2008/ Accepted 29 December 2008

Clinical trials have shown oncolytic adenoviruses to be tumor selective with minimal toxicity toward normal tissue. The virus ONYX-015, in which the gene encoding the early region 1B 55-kDa (E1B-55K) protein is deleted, has been most effective when used in combination with either chemotherapy or radiation therapy. Therefore, improving the oncolytic nature of tumor-selective adenoviruses remains an important objective for improving this form of cancer therapy. Cells infected during the G1 phase of the cell cycle with the E1B-55K deletion mutant virus exhibit a reduced rate of viral late protein synthesis, produce fewer viral progeny, and are less efficiently killed than cells infected during the S phase. Here we demonstrate that the G1 restriction imposed on the E1B-55K deletion mutant virus is due to the viral oncogene encoded by open reading frame 1 of early region 4 (E4orf1). E4orf1 has been reported to signal through the phosphatidylinositol 3'-kinase pathway leading to the activation of Akt, mTOR, and p70 S6K. Evidence presented here shows that E4orf1 may also induce the phosphorylation of Akt and p70 S6K in a manner that depends on Rac1 and its guanine nucleotide exchange factor Tiam1. Accordingly, agents that have been reported to disrupt the Tiam1-Rac1 interaction or to prevent phosphorylation of the ribosomal S6 kinase partially alleviated the E4orf1 restriction to late viral protein synthesis and enhanced tumor cell killing by the E1B-55K mutant virus. These results demonstrate that E4orf1 limits the oncolytic nature of a conditionally replicating adenovirus such as ONYX-015. The therapeutic value of similar oncolytic adenoviruses may be improved by abrogating E4orf1 function.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Medical Center Blvd., Wake Forest University School of Medicine, Winston-Salem, NC 27157-1064. Phone: (336) 716-9332. Fax: (336) 716-9928. E-mail: ornelles{at}wfubmc.edu

{triangledown} Published ahead of print on 7 January 2009.

Journal of Virology, March 2009, p. 2406-2416, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.01972-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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