Abstract
A number of vector systems have been developed for the delivery of therapeutic genes into cells (1). Many viral vectors suffer from the disadvantage of random integration into the chromosome, making the expression of the cloned genes dependent on the chromosomal context of the inserted DNA. Papillomaviruses (PVs) are potentially important vector systems because of their extrachromosomal replication in target cells. The PVs are small DNA viruses that infect humans and a wide range of animals. Human papillomaviruses (HPVs) induce benign proliferative squamous eplthelial and fibro-epithelial lesions (warts and papillomas) in their natural hosts (2). Some HPVs are also involved in the pathogenesis of anogenital cancer and, in particular, cancer of the cervix (2). Papillomaviruses contain circular, double-stranded DNA of approx 8 kb, and usually replicate extrachromosomally at a copy number estimated to be between 10 and 100 (3). The potential advantages of PV vectors include expression of cloned genes from an extrachromosomal state that may be more amenable to uniform expression and possible elimination of problems associated with integration of DNA into transcriptionally inactive regions of the cellular chromosomes. Since PV DNA is not encapsidated, it may be possible to insert larger DNA sequences into such vectors, provided the DNA can still replicate in a stable manner. Bovine papillomavirus type 1 (BPV-1) vectors have been used to produce stable cell lines expressing foreign proteins (for reviews, see refs. 4-7). The BPV-1 vectors used in these studies contained both replication and transforming genes, and in most cases, extrachromosomal replication of these vectors was accompanied by transformation of the target cells (8-12). Recent advances in our understanding of the replication and transforming genes of PVs have resulted in renewed efforts to develop vectors that can be established as stable extrachromosomal plasmids and express foreign proteins without oncogenic transformation of the host cell. The current article deals mostly with the potential of HPVs as vectors for gene therapy.
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References
Mulligan, R. C. (1993) The basic science of gene therapy. Science 260, 926–932.
zur Hausen, H. (1991) Human papillomaviruses in the pathogenesis of anogenital cancer. Virology 184, 9–13.
Lambert, P. F. (1991) Papillomavirus DNA replication. J. Viral 65, 3417–3420.
DiMaio, D (1987) Papillomavirus cloning vectors, in The Papovaviridae 2. The Papillomaviruses (Salzman, N. P. and Howley, P. M., eds.), Plenum, New York, pp. 293–319.
Sarver, N., Gruss, P., Law, M.-F., Khoury, G., and Howley, P. M. (1981) Bovine papillomavirus deoxyribonucleic acid: a novel eukaryotic cloning vector. Mel Cell Biol 1, 486–496.
Stephens, P. E. and Hentschel, C. G. (1987) The bovine papillomavirus genome and its uses as a eukaryotic vector. Biochem. J. 248, 1–11.
Waldenstrom, M., Schenstrom, K., Sollerbrant, K., and Hansson, L. (1992) Replication of bovine papillomavirus vectors in murine cells. Gene 120, 175–181.
Baker, M. D., Murialdo, H., and Shulman, M. J. (1988) Expression of an immuno-globulin light-chain gene in lymphoid cells using a bovine papillomavirus-1 (BPV-1) vector. Gene 69, 349–355.
MacGregor, G. R. and Burke, J. F (1987) Stability of a bacterial gene in a bovine papillomavirus-based shuttle vector maintained extrachromosomally in mammalian cells. J. Gen. Viral 68, 247–252.
Matthias, P., Boeger, U., Danesch, U., Schutz, G., and Bernard, H.-U (1986) Physical state, expression and regulation of two glucocorticoid-controlled genes on bovine papillomavirus vectors. J Mel Biol 187, 557–568.
Meneguzzi, G., Binetruy, B., and Cuzin, F. (1984) Plasmidial maintenance in rodent fibroblasts of a BPV-1-pBR322 shuttle vector without immediately apparent oncogenic transformation of the recipient cells. EMBO J 3, 365–371.
Sarver, N. A., Ricca, G. A., Link, J., Nathan, M. H, Newman, J, and Drohan, W. N. (1987) Stable expression of recombinant factor VIII molecules using a bovine papillomavirus vector DNA 6, 553–564.
Bedell, M. A., Jones, K. H., Grossman, S. R., and Laimins, L. A (1989) Identification of human papillomavirus type 18 transforming genes in immortalized and primary cells. J Virol. 63, 1247–1255.
Chiang, C. M., Ustav, M., Stenlund, A, Ho, T. F., Broker, T. R., and Chow, L. T. (1992) Viral E1 and E2 proteins support replication of homologous and heterologous papillomaviral origins. Proc. Natl. Acad. Sci. USA 89, 5799–5803.
Del Vecchio, A. M., Romanczuk, H., Howley, P. M, and Baker, C C (1992) Transient replication of human papillomavirus DNAs. J Virol 66, 5949–5958.
Mungal, S, Steinberg, B. M., and Taichman, L. B. (1992) Replication of plasmid-derived human papillomavirus type 11 DNA in cultured keratinocytes. J Viral 66, 3220–3224.
Ustav, M. and Stenlund, A. (1991) Transient replication of BPV-1 requires two viral polypeptides encoded by the E1 and E2 open reading frames. EMBO J 10, 449–457.
Ustav, E., Ustav, M., Szymanski, P., and Stenlund, A. (1993) The bovine papillomavirus origin of replication requires a binding sue for the E2 transcriptional activator. Proc. Natl. Acad. Sci. USA 90, 898–902.
Sverdrup, F. and Khan, S. A. (1994) Replication of human papillomavirus DNAs supported by the HPV-18 E1 and E2 proteins. J. Virol. 68, 505–509.
Gopalakrishnan, V. and Khan, S. A. (1994) The E1 protein of human papillomavuvirus type 1a is sufficient for the initiation of viral DNA replication. Proc. Natl. Acad sci USA 91, 9597–9601.
Seo, Y. S., Muller, F., Lusky, M., and Hurwitz, J. (1993) Bovine papillomavirus (BPV)-encoded E1 protein contains multiple activities required for BPV DNA replication. Proc. Natl. Acad. Sci. USA 90, 702–706.
Yang, L., Mohr, I., Fouts, E, Lim, D. A, Nohaile, M., and Botchan, M. (1993) The E1 protein of bovine papillomavirus 1 is an ATP-dependent DNA helicase. Proc. Natl. Acad. Sci. USA 90, 5086–5090.
Belyavski, M., Miller, J., and Wilson, V. (1994) The bovine papillomavirus E1 protein alters the host cell cycle and growth properties. Virology 204, 132–143.
McBride, A. A., Romanczuk, H., and Howley, P. M. (1991) The papillomavirus E2 regulatory proteins. J Biol Chem 266, 18,411–18,414.
Mohr, I. J., Clark, R, Sun, S., Androphy, E. J, MacPherson, P, and Botchan, M. R (1990) Targeting the E1 replication protein to the papillomavirus origin of replication by complex formation with the E2 transactivator. Science 250, 1694–1699.
Lusky, M., Hurwitz, J, and Seo, Y-S. (1994) The bovine papillomavirus E2 protein modulates the assembly of but is not stably maintained in a replication-competent multimeric E1-replication origin complex. Proc Natl Acad Sci USA 91, 8895–8899.
Dollard, S. C., Wilson, J. L., Demeter, L. M., Bonnez, W., Reichman, C, Broker, T. R, and Chow, L T (1992) Production of human papillomavirus and modulation of the infectious program in epithehal raft cultures. Genes Dev 6, 1131–1142.
Meyers, C., Frattini, M. G., Hudson, J B., and Laimins, L. A. (1992) Biosynthesis of human papillomavirus from a continuous cell line upon epithehal differentiation Science 251, 971–973.
Sterling, J., Stanley, M, Gatward, G, and Minson, T. (1990) Production of human papillomavirus type 16 virions in a keratinocyte cell line. J. Virol 64, 6305–6307.
Yang, N. S, Burkholder, J., Roberts, B, Martinell, B, and McCabe, D (1990) In vivo and in vitro gene transfer to mammalian somatic cells by particle bombardment. Proc Natl Acad Sci. USA 87, 9568–9572.
Chen, C. and Okayama, H. (1987) High-efficiency transformation of mammalian cells by plasmid DNA. Mol. Cell. Biol. 7, 2745–2752.
Hirt, B. (1967) Selective extraction of polyoma DNA from infected mouse cell cultures J Mol Biol 26, 365–369.
Sambrook, J, Fritsch, E. F, and Maniatis, T. (1989) Molecular Cloning—A Laboratory Manual, 2nd ed, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.
Roden, R. B S, Kirnbauer, R, Jenson, A. B, Lowy, D. R., and Schiller, J. T (1994) Interaction of papillomaviruses with the cell surface J. Viral 68, 7260–7266.
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© 1997 Humana Press Inc., Totowa, NJ
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Khan, S.A., Sverdrup, F.M. (1997). Methods for the Construction of Human Papillomavirus Vectors. In: Robbins, P.D. (eds) Gene Therapy Protocols. Methods in Molecular Medicine, vol 7. Humana, Totowa, NJ. https://doi.org/10.1385/0-89603-484-4:117
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DOI: https://doi.org/10.1385/0-89603-484-4:117
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