1887

Abstract

The observation that exposure of target cells to genotoxic stress or adenovirus infection enhances recombinant adeno-associated virus (rAAV) transduction is an important lead towards defining the rAAV transduction mechanism, and has significant implications for the exploitation of rAAV in gene therapy applications. The adenovirus-mediated enhancement of rAAV transduction has been mapped to the E4 ORF6 gene, and expression of E4 ORF6 alone has been considered necessary and sufficient to mediate this effect. Since p53 subserves an important function in the cellular response to genotoxic stress, and interacts with the E4 ORF6 gene product during adenovirus infection, we hypothesized that p53 function might be essential to the rAAV enhancement resulting from these cellular insults. In the current study, using the p53-null cell lines H1299 and Saos-2, we find that p53 is not essential to either genotoxic stress or adenovirus-mediated enhancement of rAAV transduction. We further demonstrate using HeLa, H1299 and Saos-2 cells that E4 ORF6 expression alone is not sufficient to enhance rAAV transduction and that coexpression of the adenovirus E1b 55 kDa protein is necessary. Together, these observations indicate that the mechanism by which adenovirus infection enhances rAAV transduction involves cooperative and interdependent functions of the E4 ORF6 and E1b 55 kDa proteins that are p53-independent.

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2000-12-01
2020-01-22
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References

  1. Alexander, I. E., Russell, D. W. & Miller, A. D. ( 1994; ). DNA-damaging agents greatly increase the transduction of nondividing cells by adeno-associated virus vectors. Journal of Virology 68, 8282-8287.
    [Google Scholar]
  2. Atchison, R. W., Casto, B. C. & Hammon, W. M. ( 1965; ). Adenovirus-associated defective virus particles. Science 149, 754-756.[CrossRef]
    [Google Scholar]
  3. Barker, D. D. & Berk, A. J. ( 1987; ). Adenovirus proteins from both E1B reading frames are required for transformation of rodent cells by viral infection and DNA transfection. Virology 156, 107-121.[CrossRef]
    [Google Scholar]
  4. Berns, K. I. & Rose, J. A. ( 1970; ). Evidence for a single-stranded adenovirus-associated virus genome: isolation and separation of complementary single strands. Journal of Virology 5, 693-699.
    [Google Scholar]
  5. Buller, R. M., Janik, J. E., Sebring, E. D. & Rose, J. A. ( 1981; ). Herpes simplex virus types 1 and 2 completely help adenovirus-associated virus replication. Journal of Virology 40, 241-247.
    [Google Scholar]
  6. Cutt, J. R., Shenk, T. & Hearing, P. ( 1987; ). Analysis of adenovirus early region 4-encoded polypeptides synthesized in productively infected cells. Journal of Virology 61, 543-552.
    [Google Scholar]
  7. Diller, L., Kassel, J., Nelson, C. E., Gryka, M. A., Litwak, G., Gebhardt, M., Bressac, B., Ozturk, M., Baker, S. J. & Vogelstein, B. ( 1990; ). p53 functions as a cell cycle control protein in osteosarcomas. Molecular and Cellular Biology 10, 5772-5781.
    [Google Scholar]
  8. Dobner, T., Horikoshi, N., Rubenwolf, S. & Shenk, T. ( 1996; ). Blockage by adenovirus E4orf6 of transcriptional activation by the p53 tumor suppressor. Science 272, 1470-1473.[CrossRef]
    [Google Scholar]
  9. Doucas, V., Ishov, A. M., Romo, A., Juguilon, H., Weitzman, M. D., Evans, R. M. & Maul, G. G. ( 1996; ). Adenovirus replication is coupled with the dynamic properties of the PML nuclear structure. Genes & Development 10, 196-207.[CrossRef]
    [Google Scholar]
  10. Ferrari, F. K., Samulski, T., Shenk, T. & Samulski, R. J. ( 1996; ). Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors. Journal of Virology 70, 3227-3234.
    [Google Scholar]
  11. Fisher, K. J., Gao, G. P., Weitzman, M. D., DeMatteo, R., Burda, J. F. & Wilson, J. M. ( 1996; ). Transduction with recombinant adeno-associated virus for gene therapy is limited by leading-strand synthesis. Journal of Virology 70, 520-532.
    [Google Scholar]
  12. Flotte, T. R. & Carter, B. J. ( 1995; ). Adeno-associated virus vectors for gene therapy. Gene Therapy 2, 357-362.
    [Google Scholar]
  13. Gey, G. O., Coffman, W. D. & Kubicek, M. T. ( 1952; ). Tissue culture studies of the proliferative capacity of cervical carcinoma and normal epithelium. Scientific Proceedings of the American Association for Cancer Research 12, 264.
    [Google Scholar]
  14. Goodman, S., Xiao, X., Donahue, R. E., Moulton, A., Miller, J., Walsh, C., Young, N. S., Samulski, R. J. & Nienhuis, A. W. ( 1994; ). Recombinant adeno-associated virus-mediated gene transfer into hematopoietic progenitor cells. Blood 84, 1492-1500.
    [Google Scholar]
  15. Goodrum, F. D., Shenk, T. & Ornelles, D. A. ( 1996; ). Adenovirus early region 4 34-kilodalton protein directs the nuclear localization of the early region 1B 55-kilodalton protein in primate cells. Journal of Virology 70, 6323-6335.
    [Google Scholar]
  16. Gorman, C. ( 1985; ). High efficiency gene transfer into mammalian cells. In DNA Cloning, 1st edn, pp. 143-165. Edited by D. M. Glover. Oxford & Washington, DC:IRL Press.
  17. Graham, F. L. ( 1984; ). Covalently closed circles of human adenovirus DNA are infectious. EMBO Journal 3, 2917-2922.
    [Google Scholar]
  18. Graham, F. L., Smiley, J., Russell, W. C. & Nairn, R. ( 1977; ). Characteristics of a human cell line transformed by DNA from human adenovirus type 5. Journal of General Virology 36, 59-74.[CrossRef]
    [Google Scholar]
  19. Grifman, M., Chen, N. N., Gao, G. P., Cathomen, T., Wilson, J. M. & Weitzman, M. D. ( 1999; ). Overexpression of cyclin A inhibits augmentation of recombinant adeno-associated virus transduction by the adenovirus E4orf6 protein. Journal of Virology 73, 10010-10019.
    [Google Scholar]
  20. Halbert, C. L., Alexander, I. E., Wolgamot, G. M. & Miller, A. D. ( 1995; ). Adeno-associated virus vectors transduce primary cells much less efficiently than immortalized cells. Journal of Virology 69, 1473-1479.
    [Google Scholar]
  21. Jones, N. & Shenk, T. ( 1979; ). Isolation of adenovirus type 5 host range deletion mutants defective for transformation of rat embryo cells. Cell 17, 683-689.[CrossRef]
    [Google Scholar]
  22. Laughlin, C. A., Cardellichio, C. B. & Coon, H. C. ( 1986; ). Latent infection of KB cells with adeno-associated virus type 2. Journal of Virology 60, 515-524.
    [Google Scholar]
  23. Levine, A. J. ( 1997; ). p53, the cellular gatekeeper for growth and division. Cell 88, 323-331.[CrossRef]
    [Google Scholar]
  24. Maass, G., Bogedain, C., Scheer, U., Michl, D., Horer, M., Braun-Falco, M., Volkenandt, M., Schadendorf, D., Wendtner, C. M., Winnacker, E. L., Kotin, R. M. & Hallek, M. ( 1998; ). Recombinant adeno-associated virus for the generation of autologous, gene-modified tumor vaccines: evidence for a high transduction efficiency into primary epithelial cancer cells. Human Gene Therapy 9, 1049-1059.[CrossRef]
    [Google Scholar]
  25. McLaughlin, S. K., Collis, P., Hermonat, P. L. & Muzyczka, N. ( 1988; ). Adeno-associated virus general transduction vectors: analysis of proviral structures. Journal of Virology 62, 1963-1973.
    [Google Scholar]
  26. Marton, M. J., Baim, S. B., Ornelles, D. A. & Shenk, T. ( 1990; ). The adenovirus E4 17-kilodalton protein complexes with the cellular transcription factor E2F, altering its DNA-binding properties and stimulating E1A-independent accumulation of E2 mRNA. Journal of Virology 64, 2345-2359.
    [Google Scholar]
  27. Mitsudomi, T., Steinberg, S. M., Nau, M. M., Carbone, D., D’Amico, D., Bodner, S., Oie, H. K., Linnoila, R. I., Mulshine, J. L. & Minna, J. D. ( 1992; ). p53 gene mutations in non-small-cell lung cancer cell lines and their correlation with the presence of ras mutations and clinical features. Oncogene 7, 171-180.
    [Google Scholar]
  28. Moore, M., Horikoshi, N. & Shenk, T. ( 1996; ). Oncogenic potential of the adenovirus E4orf6 protein. Proceedings of the National Academy of Sciences, USA 93, 11295-11301.[CrossRef]
    [Google Scholar]
  29. Muzyczka, N. ( 1992; ). Use of adeno-associated virus as a general transduction vector for mammalian cells. Current Topics in Microbiology and Immunology 158, 97-129.
    [Google Scholar]
  30. Nevels, M., Rubenwolf, S., Spruss, T., Wolf, H. & Dobner, T. ( 1997; ). The adenovirus E4orf6 protein can promote E1A/E1B-induced focus formation by interfering with p53 tumor suppressor function. Proceedings of the National Academy of Sciences, USA 94, 1206-1211.[CrossRef]
    [Google Scholar]
  31. Pilder, S., Moore, M., Logan, J. & Shenk, T. ( 1986; ). The adenovirus E1B-55K transforming polypeptide modulates transport or cytoplasmic stabilization of viral and host cell mRNAs. M olecular and Cellular Biology 6, 470-476.
    [Google Scholar]
  32. Querido, E., Marcellus, R. C., Lai, A., Charbonneau, R., Teodoro, J. G., Ketner, G. & Branton, P. E. ( 1997; ). Regulation of p53 levels by the E1B 55-kilodalton protein and E4orf6 in adenovirus-infected cells. Journal of Virology 71, 3788-3798.
    [Google Scholar]
  33. Richardson, W. D. & Westphal, H. ( 1984; ). Requirement for either early region 1a or early region 1b adenovirus gene products in the helper effect for adeno-associated virus. Journal of Virology 51, 404-410.
    [Google Scholar]
  34. Russell, D. W. & Kay, M. A. ( 1999; ). Adeno-associated virus vectors and hematology. Blood 94, 864-874.
    [Google Scholar]
  35. Russell, D. W., Miller, A. D. & Alexander, I. E. ( 1994; ). Adeno-associated virus vectors preferentially transduce cells in S phase. Proceedings of the National Academy of Sciences, USA 91, 8915-8919.[CrossRef]
    [Google Scholar]
  36. Russell, D. W., Alexander, I. E. & Miller, A. D. ( 1995; ). DNA synthesis and topoisomerase inhibitors increase transduction by adeno-associated virus vectors. Proceedings of the National Academy of Sciences, USA 92, 5719-5723.[CrossRef]
    [Google Scholar]
  37. Sambrook, J., Fritsch, E. F. & Maniatis, T. (1989). Molecular Cloning: A Laboratory Manual, 2nd edn, Cold Spring Harbor, NY: Cold Spring Harbor Laboratory.
  38. Samulski, R. J. & Shenk, T. ( 1988; ). Adenovirus E1B 55-Mr polypeptide facilitates timely cytoplasmic accumulation of adeno-associated virus mRNAs. Journal of Virology 62, 206-210.
    [Google Scholar]
  39. Samulski, R. J., Chang, L. S. & Shenk, T. ( 1987; ). A recombinant plasmid from which an infectious adeno-associated virus genome can be excised in vitro and its use to study viral replication. Journal of Virology 61, 3096-3101.
    [Google Scholar]
  40. Samulski, R. J., Chang, L. S. & Shenk, T. ( 1989; ). Helper-free stocks of recombinant adeno-associated viruses: normal integration does not require viral gene expression. Journal of Virology 63, 3822-3828.
    [Google Scholar]
  41. Sanlioglu, S., Duan, D. & Engelhardt, J. F. ( 1999; ). Two independent molecular pathways for recombinant adeno-associated virus genome conversion occur after UV-C and E4orf6 augmentation of transduction. Human Gene Therapy 10, 591-602.[CrossRef]
    [Google Scholar]
  42. Sarnow, P., Sullivan, C. A. & Levine, A. J. ( 1982; ). A monoclonal antibody detecting the adenovirus type 5-E1b-58Kd tumor antigen: characterization of the E1b-58Kd tumor antigen in adenovirus-infected and -transformed cells. Virology 120, 510-517.[CrossRef]
    [Google Scholar]
  43. Sarnow, P., Hearing, P., Anderson, C. W., Halbert, D. N., Shenk, T. & Levine, A. J. ( 1984; ). Adenovirus early region 1B 58000-dalton tumor antigen is physically associated with an early region 4 25000-dalton protein in productively infected cells. Journal of Virology 49, 692-700.
    [Google Scholar]
  44. Schneider-Gadicke, A. & Schwarz, E. ( 1986; ). Different human cervical carcinoma cell lines show similar transcription patterns of human papillomavirus type 18 early genes. EMBO Journal 5, 2285-2292.
    [Google Scholar]
  45. Snyder, R. O., Xiao, X. & Samulski, R. J. (1996). Production of recombinant adeno-associated viral vectors. In Current Protocols in Human Genetics, 12.0.1–12.1.24. Edited by N. Dracopoli, J. Haines, B. Krof, C. Moir, C. Morton, C. Seidman, J. Seidman & D. Smith. USA: New York: John Wiley & Sons.
  46. Steegenga, W. T., Riteco, N., Jochemsen, A. G., Fallaux, F. J. & Bos, J. L. ( 1998; ). The large E1B protein together with the E4orf6 protein target p53 for active degradation in adenovirus infected cells. Oncogene 16, 349-357.[CrossRef]
    [Google Scholar]
  47. Steele, R. J., Thompson, A. M., Hall, P. A. & Lane, D. P. ( 1998; ). The p53 tumour suppressor gene. British Journal of Surgery 85, 1460-1467.[CrossRef]
    [Google Scholar]
  48. Weitzman, M. D., Fisher, K. J. & Wilson, J. M. ( 1996; ). Recruitment of wild-type and recombinant adeno-associated virus into adenovirus replication centers. Journal of Virology 70, 1845-1854.
    [Google Scholar]
  49. Xiao, X., Li, J. & Samulski, R. J. ( 1996; ). Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. Journal of Virology 70, 8098-8108.
    [Google Scholar]
  50. Xiao, X., Li, J., McCown, T. J. & Samulski, R. J. ( 1997; ). Gene transfer by adeno-associated virus vectors into the central nervous system. Experimental Neurology 144, 113-124.[CrossRef]
    [Google Scholar]
  51. Xiao, X., Li, J. & Samulski, R. J. ( 1998; ). Production of high-titer recombinant adeno-associated virus vectors in the absence of helper adenovirus. Journal of Virology 72, 2224-2232.
    [Google Scholar]
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