Retrovirus Vectors
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RETROVIRUS VECTORS Yasuhiro Takeuchi and Massimo Pizzato Chester Beatty Laboratories The Institute of Cancer Research 237 Fulham Road, London SW3 6JB England
1. INTRODUCTION Retroviruses are enveloped viruses which contain 7–12kb RNA genomes. After virus entry to cells via specific cell-surface receptors, their genomes are reverse transcribed into double-stranded DNA and subsequently integrated into the host chromosome in the form of provirus. The provirus replicates as the host chromosome replicates and is transmitted to all of the progeny of the host cells. This ability of retroviruses to stably transfer genetic information is an attraction to use retroviruses as gene transfer vectors. Because the retrovirus genome is relatively small and well-characterised, it is possible to engineer vector packaging systems which produce vectors encoding only transgenes and does neither produce replication competent viruses (RCV) nor transfer virus structural genes. Absence of RCV is required for safety, while the lack of expression of any viral protein in recipient cells could be advantageous in many preclinical and clinical settings
as viral proteins may elicit undesirable immune responses. Most widely used retrovirus vectors to date are based on murine leukemia viruses (MLV). This chapter mainly summarises studies on MLV systems, but many principles can be applied for other retrovirus vector systems. Recent progress in the development of lentivirus vectors which, unlike MLV vectors, are able to infect non-dividing cells is also summarised. Detailed reviews on retrovirus vectors have been published elsewhere (Günzburg and Salmons, 1996; Miller, 1997; Collins and Porter, 1998).
2. DEVELOPMENT OF VECTOR SYSTEMS
2.1. Naturally Occuring Vectors Acutely transforming retroviruses in birds and nonhuman mammals can be regarded as naturally occuring retrovirus vectors. These viruses have acquired cellular Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/Plenum Publishers, New York, 2000.
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oncogenes which are transferred and spread by virus infection resulting in cell transformation and tumour formation. With the exception of some strains of Rous sarcoma virus which carry the src oncogene in addition to a full set of virus genes and therefore can replicate by themselves, most oncogenes are encoded by replication-defective virus genomes. Such oncogene-containing virus genomes lack all or part of virus structural genes but retain all necessary cis-acting sequences and can replicate as mixtures with nontransforming, nondefective “helper” viruses which provide virus proteins in trans. Thus, nature shows us a way to transfer non-viral genes to the cell using the mechanism of retrovirus replication. Development of packaging systems of retrovirus vectors started by mimicking and modifying this natural strategy. It may be interesting to note that the same strategy that has been used by “oncogenic” retroviruses is used in “cancer” gene therapy.
2.2. Design of
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