38 million people are currently living with HIV/AIDS. Although the progress in developing antiretroviral therapies (ART) has been enormous, ART is too expensive or inaccessible for a large fraction of infected individuals, and requires lifelong adherence to a treatment regimen. An HIV cure would address many of these problems, but is still missing. Our objective is to find small molecules that can inhibit or enhance the host factor-dependent transcription of the viral genome, leading to a functional cure by permanently locking out viral transcription or leading to a cure by efficiently reactivating and eliminating latent HIV provirus. Towards this goal, we will take advantage of new structural data on a critical host transcription factor complex (SEC) that is required for HIV transcription. Our recent crystal structures of SEC in complex with HIV1 Tat and TAR define protein/protein interaction surfaces and protein/RNA interaction surfaces that can be targeted by drug design and drug screening approaches. In collaboration with small molecule drug screening experts at UCSF we will screen for inhibitors of Tat and TAR binding. Together with protein-design experts we will also work towards developing Tat-mimetics as tool for Tat binding inhibitor screening and to explore the feasibility of designing novel Tatmimetics with molecular glue characteristics. Such Tat mimetics could reactivate latent provirus by replacing the function of viral Tat and enabling SEC binding to TAR RNA. The detailed structures of multiple complexes of human SEC with viral Tat and TAR RNA offer the opportunity to apply current drug screening and design methods to make significant progress towards a long-awaited HIV cure.