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Journal of Virology, March 2008, p. 3069-3077, Vol. 82, No. 6
0022-538X/08/$08.00+0     doi:10.1128/JVI.01880-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Cellular Restriction of Retrovirus Particle-Mediated mRNA Transfer{triangledown}

Melanie Galla,1 Axel Schambach,1,2 Greg J. Towers,3 and Christopher Baum1,4*

Department of Experimental Hematology, Hannover Medical School, Hannover, Germany,1 Pediatric Hematology and Oncology, Children's Hospital, Hannover Medical School, Hannover, Germany,2 Department of Infection UCL, London, United Kingdom,3 Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio4

Received 28 August 2007/ Accepted 3 January 2008

Analyzing cellular restriction mechanisms provides insight into viral replication strategies, identifies targets for antiviral drug design, and is crucial for the development of novel tools for experimental or therapeutic delivery of genetic information. We have previously shown that retroviral vector mutants that are unable to initiate reverse transcription mediate a transient expression of any sequence which replaces the gag-pol transcription unit, a process we call retrovirus particle-mediated mRNA transfer (RMT). Here, we further examined the mechanism of RMT by testing its sensitivity to cellular restriction factors and short hairpin RNAs (shRNAs). We found that both human TRIM5{alpha} and, to a lesser extent, Fv1 effectively restrict RMT if the RNA is delivered by a restriction-sensitive capsid. While TRIM5{alpha} restriction of RMT led to reduced levels of retroviral mRNA in target cells, restriction by Fv1 did not. Treatment with the proteasome inhibitor MG132 partially relieved TRIM5{alpha}-mediated restriction of RMT. Finally, cells expressing shRNAs specifically targeting the retroviral mRNA inhibited RMT particles, but not reverse-transcribing particles. Retroviral mRNA may thus serve as a translation template if not used as a template for reverse transcription. Our data imply that retroviral nucleic acids become accessible to host factors, including ribosomes, as a result of particle remodeling during cytoplasmic trafficking.

* Corresponding author. Mailing address: Department of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. Phone: 49 511-532-6067. Fax: 49 511-532-6068. E-mail: baum.christopher{at}mh-hannover.de

{triangledown} Published ahead of print on 16 January 2008.

Journal of Virology, March 2008, p. 3069-3077, Vol. 82, No. 6
0022-538X/08/$08.00+0     doi:10.1128/JVI.01880-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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