Recent Advances in Targeting the HIV-1 Tat/TAR Complex

Following seminal discoveries by Rosen and co-workers in 1985, the HIV-1 TAR has emerged as one of the most extensively studied regulatory elements of the HIV-1 genome. Located adjacent to the long terminal repeat promoter, this cis-acting motif, in conjunction with the viral Tat protein, plays a critical role in viral genomic RNA synthesis via modification of the transcription complex. As such, the Tat/TAR axis has been the subject of intense efforts aimed at developing therapeutic interventions, directed against both the protein and nucleic acid components. While these efforts have to date been largely unsuccessful, current strategies to develop a functional cure for HIV have spawned renewed interest in targeting the Tat/TAR complex as a means of impairing virus reactivation and ultimately reducing the size of the latent reservoir pool. At the same time, advances in high throughput technologies, coupled with an increased understanding of RNA biology and function, have led to the identification of novel agents with enhanced potency and selectivity against a variety of cis-acting regulatory RNAs. In this review, recent approaches utilized to identify small molecules, peptides and evolved proteins with respect to targeting HIV-1 TAR are discussed.