This application is the first revision of a competing continuation. In this revised proposal the investigators wish to pursue a gene therapy approach to the treatment of HIV that focuses on the enhancement of the natural antiviral defense pathways found in cells. They have expressed 2 genes that are controlled by the HIV LTR in target cells and have shown that these cells are protected from infection with HIV. These genes (2',5'-oligoadenylate synthetase and the p68 kinase) are normally induced by interferon and are a part of the cellular anti-viral defense mechanisms. This strategy has a number of potential advantages when compared with other gene therapy strategies: 1) because the gene products are of human origin they should not induce the host immune system: 2) because the of the lack of dsRNA in uninfected cells they should not induce toxicity in non infected cells; and 3) since these genes are of human origin the virus should not be able to develop resistance to this strategy. The inhibition of HIV-1 replication (both M-tropic and T-tropic strains) in transduced differentiated cell populations will be examined. Studies are described to determine the effects of these constructs on HIV reactivation in latently-infected cells. Combination of this strategy with conventional therapy will be examined.
