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Journal of Virology, October 2008, p. 9369-9380, Vol. 82, No. 19
0022-538X/08/$08.00+0 doi:10.1128/JVI.01054-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
A Hyperfusogenic F Protein Enhances the Oncolytic Potency of a Paramyxovirus Simian Virus 5 P/V Mutant without Compromising Sensitivity to Type I Interferon 
Maria D. Gainey,
Mary J. Manuse, and
Griffith D. Parks*
Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1064
Received 20 May 2008/ Accepted 15 July 2008
Viral fusogenic membrane proteins have been proposed as tools to increase the potency of oncolytic viruses, but there is a need for mechanisms to control the spread of fusogenic viruses in normal versus tumor cells. We have previously shown that a mutant of the paramyxovirus simian virus 5 (SV5) that harbors mutations in the P/V gene from the canine parainfluenza virus (P/V-CPI–) is a potent inducer of type I interferon (IFN) and apoptosis and is restricted for spread through normal but not tumor cells in vitro. Here, we have used the cytopathic P/V-CPI– as a backbone vector to test the hypothesis that a virus expressing a hyperfusogenic glycoprotein will be a more effective oncolytic vector but will retain sensitivity to IFN. A P/V mutant virus expressing an F protein with a glycine-to-alanine substitution in the fusion peptide (P/V-CPI–-G3A) was more fusogenic than the parental P/V-CPI– mutant. In two model prostate tumor cell lines which are defective in IFN production (LNCaP and DU145), the hyperfusogenic P/V-CPI–-G3A mutant had normal growth properties at low multiplicities of infection and was more effective than the parental P/V-CPI– mutant at cell killing in vitro. However, in PC3 cells which produce and respond to IFN, the hyperfusogenic P/V-CPI–-G3A mutant was attenuated for growth and spread. Killing of PC3 cells was equivalent between the parental P/V-CPI– mutant and the hyperfusogenic P/V-CPI–-G3A mutant. In a nude mouse model using LNCaP cells, the hyperfusogenic P/V-CPI–-G3A mutant was more effective than P/V-CPI– at reducing tumor burden. In the case of DU145 tumors, the two vectors based on P/V-CPI– were equally effective at limiting tumor growth. Together, our results provide proof of principle that a cytopathic SV5 P/V mutant can serve as an oncolytic virus and that the oncolytic effectiveness of P/V mutants can be enhanced by a fusogenic membrane protein without compromising sensitivity to IFN. The potential advantages of SV5-based oncolytic vectors are discussed.
* Corresponding author. Mailing address: Department of Microbiology and Immunology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1064. Phone: (336) 716-9083. Fax: (336) 716-9928. E-mail: gparks{at}wfubmc.edu
Published ahead of print on 30 July 2008.
Journal of Virology, October 2008, p. 9369-9380, Vol. 82, No. 19
0022-538X/08/$08.00+0 doi:10.1128/JVI.01054-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
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