Nucleic Acids Research, 1992, Vol. 20, No. 6 1293-1299
© 1992
MOLECULAR BIOLOGY |
Retroviral vectors containing putative internal ribosome entry sites: development of a polycistronic gene transfer system and applications to human gene therapy
Molecular Hematology Branch, National Heart, Lung, and Blood Institute Bethesda, MD 20892, USA 1Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health Bethesda, MD 20892, USA
Received December 13, 1991. Revised February 10, 1992. Accepted February 10, 1992.
Recombinant retroviral vectors producing multi-cistronic mRNAs were constructed. Picornavirus putative internal ribosome entry sites (IRES) were used to confer cap-independent translation of an Internal cistron. Internal clstrons were engineered by ligatlon of various lengths of the IRES of encephalomyocardltis (EMC) virus or polio virus to the E. coli chloramphenicol acetyltransferase (CAT) gene. The IRES/CAT fusions were introduced into retroviral vectors 3' to the translation stop codon of the neomycin phosphotrans-ferase (NEO) gene, and the molecular constructs transfected into retroviral vector packaging lines. Retroviral vector producer cells efficiently express the internal CAT gene product only when the full length IRES is used. Both the EMC/CAT and polio/CAT retroviral vectors produced high tfter vector supernatant capable of productive transduction of target cells. To test the generality of this gene transfer system, a retroviral vector containing an IRES fusion to the human adenosine deaminase (ADA) gene was constructed. Producer cell supernatant was used to transduce NIH/3T3 cells, and transduced cells were shown to express NEO, and ADA. Novel three-gene-containing retroviral vectors were constructed by introducing the EMC/ADA fusion into either an existing internal-promoter-containing vector, or a polio/CAT biclstronic vector. Producer cell clones of the three-gene vectors synthesize all three gene products, were of high titer, and could productively transduce NIH/3T3 cells. By utilizing cap-independent translation units, IRES vectors can produce polycistronic mRNAs which enhance the ability of retrovlral-mediated gene transfer to engineer cells to produce multiple foreign proteins.
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