This proposal seeks to develop transcriptional blockades of the HIV-1 lifecycle. The ability to selectively manipulate the transcription of genes controlling the HIV-1 lifecycle is anticipated to have a significant impact on both our understanding of this virus as well as the treatment of the disease it causes. The study proposed here capitalizes on our development of designed transcription factors that enable activation or repression of endogenous genes. Currently no other gene therapy strategy provides the means of both effectively knocking out and up-regulating the expression of an endogenous gene. Polydactyl zinc finger proteins can now be prepared that recognize 18 bp DNA target sequences with high affinity and specificity When fused to activation or repression domains, these proteins become potent regulators of the transcriptional activity of the target gene. This proposal focuses on the use of our transcriptional regulators to specifically modulate transcription of HIV-1 and host genes essential to its lifecycle. We aim to explore the potential of targeted gene modulation as a gene-based therapeutic strategy for the treatment of HIV-1 disease as well as a unique gene discovery tool for the identification of transcriptional modifiers of host genes essential to the virus. A genome-wide transcriptional modulation strategy will be developed and applied to the search for novel targets for therapeutic intervention. The discovery of novel host proteins key to the viral lifecycle could result in the development of a new class of HIV-1 drugs since these proteins could serve as targets for the development of traditional small molecule drugs. With selective and potent transcriptional regulators we will address the potential of designed transcriptional regulators to prevent or otherwise alter the course of HIV-1 infection in primary T cells and monocytes derived from CD34+ cells. The net result of this study should be an increased understanding of HIV-1 gene regulation, the discovery of novel molecular targets, and the development of a therapeutic strategy to treat HIV-1 disease.