title: Jaagsiekte sheep retrovirus and enzootic nasal tumor virus promoters drive gene expression in all airway epithelial cells of mice but only induce tumors in the alveolar region of the lungs.
abstract: Jaagsiekte sheep retrovirus (JSRV) induces tumors in the distal airways of sheep and goats, while the closely related enzootic nasal tumor virus type 1 (ENTV-1) and ENTV-2 induce tumors in the nasal epithelium of sheep and goats, respectively. When expressed using a strong Rous sarcoma virus promoter, the envelope proteins of these viruses induce tumors in the respiratory tract of mice, but only in the distal airway. To examine the role of the retroviral long terminal repeat (LTR) promoters in determining tissue tropism, adeno-associated virus (AAV) vectors expressing alkaline phosphatase under the control of the JSRV, ENTV-1, or ENTV-2 LTRs were generated and administered to mice. The JSRV LTR was active in all airway epithelial cells, while the ENTV LTRs were active in the nasal epithelium and alveolar type II cells but poorly active in tracheal and bronchial epithelial cells. When vectors were administered systemically, the ENTV-1 and -2 LTRs were inactive in major organs examined, whereas the JSRV showed high-level activity in the liver. When a putative transcriptional enhancer from the 3' end of the env gene was inserted upstream of the JSRV and ENTV-1 LTRs in the AAV vectors, a dramatic increase in transgene expression was observed. However, intranasal administration of AAV vectors containing any combination of ENTV or JSRV LTRs and Env proteins induced tumors only in the lower airway. Our results indicate that mice do not provide an adequate model for nasal tumor induction by ENTV despite our ability to express genes in the nasal epithelium.
authors: Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
authors: Darrick L
authors: DL
authors: Yu
authors: Nicolle M
authors: NM
authors: Linnerth-Petrik
authors: Christine L
authors: CL
authors: Halbert
authors: Scott R
authors: SR
authors: Walsh
authors: A Dusty
authors: AD
authors: Miller
authors: Sarah K
authors: SK
authors: Wootton
references: J Gen Virol. 2003 Aug;84(Pt 8):2245-2252
references: 12867657
references: Virology. 2002 Jan 5;292(1):87-97
references: 11878911
references: J Virol. 1999 May;73(5):3986-93
references: 10196294
references: J Virol. 2003 Mar;77(5):2850-8
references: 12584308
references: Bioessays. 2003 Oct;25(10):930-9
references: 14505360
references: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4443-8
references: 11296287
references: Curr Top Microbiol Immunol. 2003;275:81-115
references: 12596896
references: J Virol. 2009 May;83(9):4591-604
references: 19244321
references: J Virol. 2009 Dec;83(23):12499-511
references: 19776134
references: Cell. 1983 Jul;33(3):705-16
references: 6307525
references: Virus Genes. 2007 Oct;35(2):303-12
references: 17268841
references: J Virol. 2006 Aug;80(16):8069-80
references: 16873263
references: Nature. 2005 Apr 14;434(7035):904-7
references: 15829964
references: Hum Gene Ther. 2007 Apr;18(4):344-54
references: 17430088
references: Retrovirology. 2006 Dec 19;3:94
references: 17177996
references: J Gen Virol. 2006 Sep;87(Pt 9):2685-2692
references: 16894209
references: J Biol Chem. 1994 Aug 5;269(31):19691-4
references: 8051046
references: Mol Ther. 2005 Mar;11(3):460-9
references: 15727943
references: Mol Ther. 2000 Jan;1(1):88-95
references: 10933916
references: J Virol. 2000 Sep;74(17):8065-76
references: 10933716
references: J Virol. 1997 Aug;71(8):5932-41
references: 9223483
references: Nucleic Acids Res. 1984 Aug 24;12(16):6427-42
references: 6089114
references: FEBS Lett. 2009 Apr 17;583(8):1386-90
references: 19336234
references: J Virol. 2000 May;74(10):4698-704
references: 10775607
references: Nat Protoc. 2007;2(9):2092-104
references: 17853864
references: J Gen Virol. 1977 Jul;36(1):59-74
references: 886304
references: J Virol. 2005 Jan;79(1):87-94
references: 15596804
references: J Virol. 2006 Sep;80(18):9322-5
references: 16940543
references: Mol Cell Biol. 1982 Nov;2(11):1331-8
references: 6298596
references: Curr Top Microbiol Immunol. 2003;275:55-79
references: 12596895
references: J Virol. 2000 Jul;74(13):5776-87
references: 10846056
references: J Virol. 1995 Nov;69(11):7054-60
references: 7474125
references: Curr Gene Ther. 2001 Jul;1(2):137-47
references: 12108951
references: J Virol. 1998 Dec;72(12):9795-805
references: 9811715
references: Virology. 2008 Mar 15;372(2):398-408
references: 18054063
references: Curr Top Microbiol Immunol. 2003;275:201-23
references: 12596900
references: Mol Ther. 2008 Dec;16(12):1960-7
references: 18827805
references: Nat Biotechnol. 2002 Jul;20(7):697-701
references: 12089554
references: J Virol. 1999 Aug;73(8):6964-72
references: 10400795
references: J Virol. 2002 Mar;76(5):2141-9
references: 11836391
references: J Virol. 1999 Dec;73(12):9803-9
references: 10559291
references: Virus Res. 2010 Jul;151(1):74-87
references: 20398709