Discovery and mechanistic study of HIV-1 transcriptional inhibitors from natural and synthetic products

There is currently no safe, scalable cure for HIV-1 infection due to the persistence of a latent viral reservoir. The Block-and-Lock strategy to achieve drug-free HIV remission requires promotion of a durable, deep latent state from which dormant HIV does not reactivate. However, there are currently no licensed HIV inhibitors that target expression from the latent reservoir. Factors that are required for efficient viral transcription, such as the HIV protein Tat and the host factor CDK9, are potential targets for Block-and-Lock approaches. My thesis describes an effort to discover novel antivirals that prevent expression from latently infected cells and inhibit viral replication. I describe the identification of natural and synthetic inhibitors of HIV Tat-mediated transcription, the investigation of their molecular mechanisms, and their potential as Block-and-Lock agents. The work presented here informs the development of future HIV drug-free remission strategies and identifies CDK9 as a potential target for Block-and-Lock strategies.