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Journal of Virology, July 2006, p. 7070-7078, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.00020-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Tissue- and Tumor-Specific Targeting of Murine Leukemia Virus-Based Replication-Competent Retroviral Vectors

Christian Metzl,1,2 Daniela Mischek,1 Brian Salmons,3 Walter H. Günzburg,1,2* Matthias Renner,3 and Daniel Portsmouth1,2

Research Institute for Virology and Biomedicine, University of Veterinary Medicine, Vienna, Austria,1 Christian-Doppler Laboratory for Gene Therapeutic Vector Development, Vienna, Austria,2 Austrianova Biotechnology GmbH, Vienna, Austria3

Received 4 January 2006/ Accepted 3 May 2006

Replication-competent retrovirus vectors based on murine leukemia virus (MLV) have been shown to effectively transfer therapeutic genes over multiple serial infections in cell culture and through solid tumors in vivo with a high degree of genomic stability. While simple retroviruses possess a natural tumor selectivity in that they can transduce only actively dividing cells, additional tumor-targeting strategies would nevertheless be advantageous, since tumor cells are not the only actively dividing cells. In this study, we used the promiscuous murine cytomegalovirus promoter, a chimeric regulatory sequence consisting of the hepatitis B virus enhancer II and the human {alpha}1-antitrypsin (EII-Pa1AT) promoter, and a synthetic regulatory sequence consisting of a series of T-cell factor binding sites named the CTP4 promoter to generate replicating MLV vectors, whereby the last two are transcriptionally restricted to liver- and ß-catenin/T-cell factor-deregulated cells, respectively. When the heterologous promoters were used to replace almost the entire MLV U3 region, including the MLV TATA box, vector replication was inefficient since nascent virus particle production from infected cells was greatly decreased. Fusion of the heterologous promoters lacking the TATA box to the MLV TATA box, however, generated vectors which replicated with almost-wild-type kinetics throughout permissive cells while exhibiting low or negligible spread in nonpermissive cells. The genomic stability of the vectors was shown to be comparable to that of a similar vector containing wild-type MLV long terminal repeats, and tropism analysis over repeated infection cycles showed that the targeted vectors retained their original specificity.

* Corresponding author. Mailing address: Research Institute for Virology and Biomedicine, University of Veterinary Medicine, Veterinaerplatz 1, A-1210 Vienna, Austria. Phone: 43-1-25077-2301. Fax: 43-1-25077-2390. E-mail: walter.guenzburg{at}vu-wien.ac.at.

Journal of Virology, July 2006, p. 7070-7078, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.00020-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Schon, U., Diem, O., Leitner, L., Gunzburg, W. H., Mager, D. L., Salmons, B., Leib-Mosch, C. (2009). Human Endogenous Retroviral Long Terminal Repeat Sequences as Cell Type-Specific Promoters in Retroviral Vectors. J. Virol. 83: 12643-12650 [Abstract] [Full Text]  
  • Paar, M., Schwab, S., Rosenfellner, D., Salmons, B., Gunzburg, W. H., Renner, M., Portsmouth, D. (2007). Effects of Viral Strain, Transgene Position, and Target Cell Type on Replication Kinetics, Genomic Stability, and Transgene Expression of Replication-Competent Murine Leukemia Virus-Based Vectors. J. Virol. 81: 6973-6983 [Abstract] [Full Text]  


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