The references cited herein are not admitted to be prior art to the claimed invention.
Adenoviral vectors provide a vehicle for introducing nucleic acids into a cell in vitro and in vivo. Over 100 different serotypes, of which 47 are of human origin, have been reported. (Hierholzer, et al., J. infect. Dis. 159:804–813, 1988.) Adenoviruses type 2 and 5 used to produce adenoviral vectors are well characterized.
A human adenovirus contains a 5′ inverted terminal repeat (ITR); a packaging signal; region E1 made up of the early regions E1A and E1B; region E2; region E3, region E4; the late regions L1–L5; and a 3′ ITR. Regions E1 and E4 contain regulatory proteins, region E2 encodes proteins required for replication, and the L region encodes for the structural proteins of the virus. The E3 region is dispensable for virus growth in vitro. (Hitt, et al., Advances in Pharmacology 40:137–206, 1996.)
A replicating viral vector based on the adenovirus must contain adenovirus cis elements needed for replication. Packaging also requires cis elements on the vector whereas the necessary proteins can be supplied in trans. In trans supplementation can be brought about by specialized cells and/or additional viruses producing the needed proteins. (Hitt, et al., Advances in Pharmacology 40:137–206, 1996.)
Different types of adenoviral vectors have been developed including those lacking one or more components of the adenoviral genome. An adenoviral vector produced without components of the adenoviral genome provides advantages such as in increasing the amount of foreign nucleic acid that can be included with the adenoviral vector and removing adenoviral genes whose expression can have detrimental effects. (Hitt, et al., Advances in Pharmacology 40:137–206, 1996.)
Adenoviral vectors lacking all viral protein-coding sequences have been developed. These vectors require supplementation of viral regulatory and structural proteins supplied in trans for packaging and rescue. A second adenovirus carrying genes necessary for virus growth can be used to provide in trans the required supplementation of proteins. (Mitani, et al., Proc. Natl. Acad. Sci. USA 92:3854–3858, 1995; Fisher, et al., Virology 217:11–22, 1996; Kochanek, et al., Proc. Natl. Acad. Sci. USA 93:5731–5736, 1996; Parks, et al., Proc. Natl. Acad. Sci. USA 93:13565–13570, 1996; Parks, et al., J. Virology 71(4):3293–3298, 1997; and Schiedner, et al., Nature Genetics 18:180–183, 1998.)