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Journal of Virology, December 2002, p. 12783-12791, Vol. 76, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.24.12783-12791.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Tissue-Specific Transcriptional Targeting of a Replication-Competent Retroviral Vector

Christopher R. Logg,1,2 Aki Logg,1 Robert J. Matusik,3 Bernard H. Bochner,4 and Noriyuki Kasahara1,2,5*

Institute for Genetic Medicine,1 Departments of Pathology,2 Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033,5 Department of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232,3 Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York 100214

Received 12 April 2002/ Accepted 13 September 2002

The inability of replication-defective viral vectors to efficiently transduce tumor cells in vivo has prevented the successful application of such vectors in gene therapy of cancer. To address the need for more efficient gene delivery systems, we have developed replication-competent retroviral (RCR) vectors based on murine leukemia virus (MLV). We have previously shown that such vectors are capable of transducing solid tumors in vivo with very high efficiency. While the natural requirement of MLV infection for cell division imparts a certain degree of specificity for tumor cells, additional means for confining RCR vector replication to tumor cells are desirable. Here, we investigated the parameters critical for successful tissue-specific transcriptional control of RCR vector replication by replacing various lengths of the MLV enhancer/promoter with sequences derived either from the highly prostate-specific probasin (PB) promoter or from a more potent synthetic variant of the PB promoter. We assessed the transcriptional specificity of the resulting hybrid long terminal repeats (LTRs) and the cell type specificity and efficiency of replication of vectors containing these LTRs. Incorporation of PB promoter sequences effectively restricted transcription from the LTR to prostate-derived cells and imparted prostate-specific RCR vector replication but required the stronger synthetic promoter and retention of native MLV sequences in the vicinity of the TATA box for optimal replicative efficiency and specificity. Our results have thus identified promoter strength and positioning within the LTR as important determinants for achieving both high transduction efficiency and strict cell type specificity in transcriptionally targeted RCR vectors.

* Corresponding author. Mailing address: Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, 2250 Alcazar St., CSC 240, Los Angeles, CA 90033. Phone: (323) 442-2099. Fax: (323) 442-2764. E-mail: kasahara{at}usc.edu.

Journal of Virology, December 2002, p. 12783-12791, Vol. 76, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.24.12783-12791.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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