The objectives of this project are 1) to dissect the regulatory mechanisms responsible for HIV-1 replication and based on these findings 2) to develop molecular based strategies for the treatment of AIDS. To accomplish these objectives, we have used various technologies including the development of transgenic models for HIV-1 pathogenesis, development of transgenic mice with potentially useful gene therapeutic constructs, in vitro assays for viral molecular interference, and in vivo methods to explore factors responsible for HIV mRNA processing and transcription. Our studies have identified tissue-specific cellular factors that regulate viral gene expression and the processing of viral mRNA. We have developed transgenic mouse lines that express potentially """"""""protective genes"""""""" including an HIV-targeted ribozyme and a gene that expresses molecular decoys for the transactivator of HIV-1 Tat. We have developed methods to explore natural viral interference properties to develop strategies to inhibit HIV-1 replication. Finally, we have utilized our exisiting transgenic models of HIV-associated nephropathy, AIDS related cutaneous proliferative diseases, and growth retardation in young animals to explore the efficacy of systemic antisense oligonucleotide therapy. Ongoing studies are designed to identify tissue-specific """"""""suppressors"""""""" and """"""""activators"""""""" that may be useful in controlling viral replication, the continued use of transgenic modeling for pathogenesis and therapy, the identification of DNA transporters and the development of novel molecular therapeutic approaches for the treatment of AIDS.
