This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shah, A. C.
Right arrow Articles by Markert, J. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shah, A. C.
Right arrow Articles by Markert, J. M.

 Previous Article  |  Next Article 

Journal of Virology, August 2006, p. 7308-7315, Vol. 80, No. 15
0022-538X/06/$08.00+0     doi:10.1128/JVI.00725-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Serial Passage through Human Glioma Xenografts Selects for a {Delta}{gamma}134.5 Herpes Simplex Virus Type 1 Mutant That Exhibits Decreased Neurotoxicity and Prolongs Survival of Mice with Experimental Brain Tumors

Amish C. Shah,1 Kathleen H. Price,2 Jacqueline N. Parker,2 Sharon L. Samuel,2 Sreelatha Meleth,5 Kevin A. Cassady,2 G. Yancey Gillespie,3,4 Richard J. Whitley,2,5,6 and James M. Markert1,2,3*

Departments of Physiology and Biophysics,1 Pediatrics and Infectious Diseases,2 Surgery and Neurosurgery,3 Cell Biology and Anatomy,4 Medicine,5 Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 352336

Received 10 April 2006/ Accepted 19 May 2006

Previous studies have described in vitro serial passage of a {Delta}{gamma}134.5 herpes simplex virus type 1 (HSV-1) strain in SK-N-SH neuroblastoma cells and selection of mutants that have acquired the ability to infect and replicate in this previously nonpermissive cell line. Here we describe the selection of a mutant HSV-1 strain by in vivo serial passage, which prolongs survival in two separate experimental murine brain tumor models. Two conditionally replication-competent {Delta}{gamma}134.5 viruses, M002, which expresses murine interleukin-12, and its parent virus, R3659, were serially passaged within human malignant glioma D54-MG cell lines in vitro or flank tumor xenografts in vivo. The major findings are (i) viruses passaged in vivo demonstrate decreased neurovirulence, whereas those passaged in vitro demonstrate a partial recovery of the neurovirulence associated with HSV-1; and (ii) vvD54-M002, the virus selected after in vivo serial passage of M002 in D54-MG tumors, improves survival in two independent murine brain tumor models compared to the parent (unpassaged) M002. Additionally, in vitro-passaged, but not in vivo-passaged, M002 displayed changes in the protein synthesis profile in previously nonpermissive cell lines, as well as early US11 transcription. Thus, a mutant HSV-1 strain expressing a foreign gene can be selected for enhanced antitumor efficacy via in vivo serial passage within flank D54-MG tumor xenografts. The enhanced antitumor efficacy of vvD54-M002 is not due to restoration of protein synthesis or early US11 expression. This finding emphasizes the contribution of the in vivo tumor environment for selecting novel oncolytic HSV specifically adapted for tumor cell destruction in vivo.

* Corresponding author. Mailing address: University of Alabama at Birmingham, Division of Neurosurgery, FOT 1050, 510 20th Street South, Birmingham, AL 35294-3410. Phone: (205) 975-6985. Fax: (205) 975-3203. E-mail: jmarkert{at}uabmc.edu.

Journal of Virology, August 2006, p. 7308-7315, Vol. 80, No. 15
0022-538X/06/$08.00+0     doi:10.1128/JVI.00725-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»