Replication-competent adenoviral vectors
This invention provides improved replication-competent adenoviral vectors. The improved vectors have both a hybrid regulatory unit that provides for high level transgene expression. The vectors can be use, e.g., for therapeutic or prophylactic purposes.
1. A method of inducing an immune response to an antigen of interest encoded by a transgene, the method comprising administering to a subject an immunizing composition comprising:
(a) an adenovirus vector comprising an endogenous adenovirus tripartite leader sequence and a hybrid expression cassette, wherein the hybrid expression cassette comprises a cytomegalovirus (CMV) immediate early promoter, a second adenovirus tripartite leader sequence, and a transgene, and wherein the adenovirus vector is replication-competent; and (b) a pharmaceutically acceptable carrier or excipient.
2. The method of claim 1 , wherein the adenovirus vector is selected from the group consisting of adenovirus type 2, adenovirus type 4, adenovirus type 5, and adenovirus type 7.
3. The method of claim 2 , wherein the adenovirus vector is adenovirus type 2.
4. The method of claim 2 , wherein the adenovirus vector is adenovirus type 4.
5. The method of claim 2 , wherein the adenovirus vector is adenovirus type 5.
6. The method of claim 2 , wherein the adenovirus vector is adenovirus type 7.
7. The method of claim 1 , wherein the adenovirus vector lacks a functional E3 region.
8. The method of claim 7 , wherein the vector is deleted in the E3 region.
9. The method of claim 1 , wherein the transgene is an HIV gene.
10. The method of claim 9 , wherein the HIV gene is an HIV regulatory gene.
11. The method of claim 10 , wherein the HIV regulatory gene encodes Nef or Tat.
12. The method of claim 11 , wherein the HIV regulatory gene encodes Nef.
13. The method of claim 12 , wherein Nef is not myristoylated.
14. The method of claim 11 , wherein the HIV regulatory gene encodes Tat.
15. The method of claim 14 , wherein the Tat lacks transactivation function.
16. The method of claim 9 , wherein the HIV gene is an HIV structural gene.
17. The method of claim 16 , wherein the HIV structural gene encodes Gag or Env.
18. The method of claim 8 , wherein the hybrid expression cassette is inserted into the deleted E3 region.
19. The method of claim 1 , wherein the second adenovirus tripartite leader sequence is a spliced tripartite leader sequence.
20. The method of claim 1 , wherein the second adenovirus tripartite leader sequence comprises the sequence of SEQ ID NO: 1.
21. The method claim 1 , wherein the second adenovirus tripartite leader sequence comprises the sequence of SEQ ID NO: 2.