Targeting the HIV RNA genome: High-hanging fruit only needs a longer ladder

Abstract

Small molecules targeting the enzymes responsible for human immunodeficiency virus (HIV) maturation, DNA synthesis and its subsequent chromosomal integration as ribonucleotide-free double-stranded DNA remain the mainstay of combination antiretroviral therapy. For infected individuals harboring drugsusceptible virus, this approach has afforded complete or near-complete viral suppression. However, in the absence of a curative strategy, the predictable emergence of drug-resistant variants requires continued development of improved antiviral strategies, inherent to which is the necessity of identifying novel targets. Regulatory elements that mediate transcription, translation, nucleocytoplasmic transport, dimerization, packaging and reverse transcription of the (+) strand RNA genome should now be considered viable targets for small molecule, peptide- and oligonucleotide- based therapeutics. Where target specificity and cellular penetration and toxicity have been the primary obstacle to successful “macromolecule therapeutics”, this chapter summarizes (a) novel approaches targeting RNA motifs whose three-dimensional structure is critical for biological function and consequently may be less prone to resistance-conferring mutations and (b) improved methods for delivery.