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Journal of Virology, August 2001, p. 6989-6998, Vol. 75, No. 15
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.15.6989-6998.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Genomic Stability of Murine Leukemia Viruses Containing Insertions at the Env-3' Untranslated Region Boundary

Christopher R. Logg,1 Aki Logg,1 Chien-Kuo Tai,1 Paula M. Cannon,2 and Noriyuki Kasahara1,2,*

Department of Pathology and Institute for Genetic Medicine1 and Department of Biochemistry and Molecular Biology,2 University of Southern California School of Medicine, Los Angeles, California 90033

Received 17 January 2001/Accepted 4 May 2001

Retroviruses containing inserts of exogenous sequences frequently eliminate the inserted sequences upon spread in susceptible cells. We have constructed replication-competent murine leukemia virus (MLV) vectors containing internal ribosome entry site (IRES)-transgene cassettes at the env-3' untranslated region boundary in order to examine the effects of insert sequence and size on the loss of inserts during viral replication. A virus containing an insertion of 1.6 kb replicated with greatly attenuated kinetics relative to wild-type virus and lost the inserted sequences in a single infection cycle. In contrast, MLVs containing inserts of 1.15 to 1.30 kb replicated with kinetics only slightly attenuated compared to wild-type MLV and exhibited much greater stability, maintaining their genomic integrity over multiple serial infection cycles. Eventually, multiple species of deletion mutants were detected simultaneously in later infection cycles; once detected, these variants rapidly dominated the population and thereafter appeared to be maintained at a relative equilibrium. Sequence analysis of these variants identified preferred sites of recombination in the parental viruses, including both short direct repeats and inverted repeats. One instance of insert deletion through recombination with an endogenous retrovirus was also observed. When specific sequences involved in these recombination events were eliminated, deletion variants still arose with the same kinetics upon virus passage and by apparently similar mechanisms, although at different locations in the vectors. Our results suggest that while lengthened, insert-containing genomes can be maintained over multiple replication cycles, preferential deletions resulting in loss of the inserted sequences confer a strong selective advantage.

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

Journal of Virology, August 2001, p. 6989-6998, Vol. 75, No. 15
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.15.6989-6998.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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Copyright © 2001 by the American Society for Microbiology. All rights reserved.