Adenoviruses are double-stranded DNA viruses that have been isolated from a wide variety of avian and mammalian species, including human, swine, cow and sheep. The adenoviruses cause enteric or respiratory infection in humans as well as in domestic and laboratory animals.
At least 47 serotypes of human adenoviruses have been described. Reviews of the most common serotypes associated with particular diseases have been published. See for example, Foy H. M. (1989) Adenoviruses In Evans, AS (ed). Viral Infections of Humans. New York, Plenum Publishing, pp 77-89 and Rubin B. A. (1993) Clinical picture and epidemiology of adenovirus infections, Acta Microbiol. Hung 40:303-323. The complete genome sequence of human adenovirus 5 is disclosed in GenBank accession number M73260. The complete genome sequence of human adenovirus 2 is disclosed in GenBank accession number J01917.
Porcine adenovirus (PAV) infection has been associated with encephalitis, pneumonia, kidney lesions and diarrhea. See Derbyshire (1992) In: Diseases of Swine (ed. Leman et al.), 7th edition, Iowa State University Press, Ames, Iowa. pp. 225-227. It has been shown that PAV is capable of stimulating both humoral response and mucosal antibody responses in the intestine of infected piglets. Tuboly et al. (1993) Res. in Vet. Sci. 54:345-350. Cross-neutralization studies have indicated the existence of at least five serotypes of PAV. See Derbyshire et al. (1975) J. Comp. Pathol. 85:437-443; and Hirahara et al. (1990) Jpn. J. Vet. Sci. 52:407-409. Previous studies of the PAV genome have included the determination of restriction maps for PAV Type 3 (PAV-3) and cloning of restriction fragments representing the complete genome of PAV-3. See Reddy et al. (1993) Intervirology 36:161-168. In addition, restriction maps for PAV-1 and PAV-2 have been determined. See Reddy et al. (1995b) Arch. Virol. 140:195-200.
Nucleotide sequences have been determined for segments of the genome of various PAV serotypes. Sequences of the E3, pVIII and fiber genes of PAV-3 were determined by Reddy et al. (1995) Virus Res. 36:97-106. The E3, pVIII and fiber genes of PAV-1 and PAV-2 were sequenced by Reddy et al. (1996) Virus Res. 43:99-109, while the PAV-4 E3, pVIII and fiber gene sequences were determined by Kleiboeker (1994) Virus Res. 31:17-25. The PAV-4 fiber gene sequence was determined by Kleiboeker (1995) Virus Res. 39:299-309. Inverted terminal repeat (ITR) sequences for all five PAV serotypes (PAV-1 through PAV-5) were determined by Reddy et al. (1995) Virology 212:237-239. The PAV-3 penton sequence was determined by McCoy et al. (1996) Arch. Virol. 141:1367-1375. The nucleotide sequence of the E1 region of PAV-4 was determined by Kleiboeker (1995) Virus Res. 36:259-268. The sequence of the protease (23K) gene of PAV-3 was determined by McCoy et al. (1996) DNA Seq. 6:251-254. The sequence of the PAV-3 hexon gene (and the 14 N-terminal codons of the 23K protease gene) has been deposited in the GenBank database under accession No. U34592. The sequence of the PAV-3 100K gene has been deposited in the GenBank database under accession No. U82628. The sequence of the PAV-3 E4 region has been determined by Reddy et al. (1997) Virus Genes 15:87-90. The transcriptional map and complete DNA sequence of PAV-3 genome was reported (Reddy et al., 1998, Virus Res.58::97-106 and Reddy et al., 1998, Virology 251:414-426). Vrati et al. (1995, Virology, 209:400-408) disclose sequences for ovine adenovirus. U.S. Pat. No. 6,492,343 discloses PAV expression and vaccine systems.
BAV3 was first isolated in 1965 and is the best characterized of the BAV genotypes, containing a genome of approximately 35 kb (Kurokawa et al (1978) J. Virol. 28:212-218). Reddy et al. (1998, Journal of Virology, 72:1394) disclose nucleotide sequence, genome organization, and transcription map of BAV3. Reddy et al. (1999, Journal of Virology, 73: 9137) disclose a replication-defective BAV3 as an expression vector. BAV3, a representative of subgroup 1 of BAVs (Bartha (1969) Acta Vet. Acad. Sci. Hung. 19:319-321), is a common pathogen of cattle usually resulting in subclinical infection (Darbyshire et al. (1965). J. Comp. Pathol. 75:327-330), though occasionally associated with a more serious respiratory tract infection (Darbyshire et al., 1966 Res. Vet. Sci. 7:81-93; Mattson et al., 1988 J. Vet Res 49:67-69). Like other adenoviruses, BAV3 is a non-enveloped icosahedral particle of 75 nm in diameter (Niiyama et al. (1975) J. Virol. 16:621-633) containing a linear double-stranded DNA molecule. BAV3 can produce tumors when injected into hamsters (Darbyshire, 1966 Nature 211:102) and viral DNA can efficiently effect morphological transformation of mouse, hamster or rat cells in culture (Tsukamoto and Sugino, 1972 J. Virol. 9:465-473; Motoi et al., 1972 Gann 63:415-418). Cross hybridization was observed between BAV3 and human adenovirus type 2 (HAd2) (Hu et al., 1984 J. Virol. 49:604-608) in most regions of the genome including some regions near but not at the left end of the genome. Bovine adenovirus expression and vaccine systems are disclosed in for example, U.S. Pat. Nos. 5,820,868 and 6,001,591.
For general background references regarding adenovirus and development of adenoviral vector systems, see Graham et al. (1973) Virology 52:456-467; Takiff et al. (1981) Lancet 11:832-834; Berkner et al. (1983) Nucleic Acid Research 11: 6003-6020; Graham (1984) EMBO J. 3:2917-2922; Bett et al. (1993) J. Virology 67:5911-5921; and Bett et al. (1994) Proc. Natl. Acad. Sci. USA 91:8802-8806.
For a review of adenoviruses and adenovirus replication, see Shenk, T. and Horwitz, M. S., Virology, third edition, Fields, B. N. et al., eds., Raven Press Limited, New York (1996), Chapters 67 and 68, respectively.
Adenoviral vectors are divided into helper-independent and helper-dependent groups based on the region of the adenoviral genome used for the insertion of transgenes. Helper-dependent vectors are usually made by deletion of E1 sequences and substitution of foreign DNA, and are produced in complementing human cell lines that constitutively express E1 proteins. Graham et al. (1977) J. Gen. Virol. 36:59-74; Fallaux et al. (1996) Hum. Gene Ther. 7:215-222; Fallaux et al. (1998) Hum. Gene Ther. 9:1909-1917. An adenovirus E1A region is described in Darbyshire (1966, Nature 211:102) and Whyte et al., 1988, J. Virol. 62:257-265.
Though E1-deleted viruses do not replicate in cells that do not express E1 proteins, the viruses can express foreign proteins in these cells, provided the genes are placed under the control of a constitutive promoter. Xiang et al. (1996) Virology 219:220-227. Vaccination of animals with adenovirus recombinants containing inserts in the E1 region induced a systemic immune response and provided protection against subsequent challenge. Imler et al (1995) Hum. Gene Ther. 6:711-721; Imler et al. (1996) Gene Therap 3:75-84. This type of expression vector provides a significant safety profile to the vaccine as it eliminates the potential for dissemination of the vector within the vaccine and therefore, the spread of the vector to non-vaccinated contacts or to the general environment. However, the currently used human adenovirus (HAV) based vectors are endemic in most populations, which provides an opportunity for recombination between the helper-dependent viral vectors and wild type viruses.
United States Patent Application Publication 20020019051 discloses chimeric adenoviral vectors. Morsy et al. (1998, P.N.A.S. USA 95:7866-7871); Kochanek et al. (1996 P.N.A.S. USA 93:5731-5736); Clemens et al. (1998, Gene Therapy 3:965-972); and Parks et al.(1996, P.N.A.S. USA 93:13565-13570) disclose adenovirus vectors.
There remains a need for improved adenoviral vectors, especially adenoviral vectors for expression of transgenes in mammalian cells, and for the development of effective recombinant adenovirus vectors for use in immunization and expression systems.
All references and patent publications disclosed herein are hereby incorporated herein in their entirety by reference.