Infection with HIV disproportionately affects drug dependent individuals. Furthermore, due to a variety of factors including comorbid conditions, decreased compliance, and increased development of resistance, the effectiveness of currently available HIV treatments is reduced in this population. The need for new ways of targeting HIV is therefore particularly acute in this population. However, despite the wealth of ongoing research in HIV drug development, most new drug candidates continue to target only a few well-defined protein domains, chosen for their functional importance in HIV replication. Targeting the RNA genome itself in a structure-directed manner presents an opportunity to greatly expand the repertoire of potential target sites for anti-HIV therapeutics. The long term goals of this project are to investigate new mechanisms of inhibiting HIV by targeting its RNA genome. To accomplish this, I will combine the unique structure-probing technologies developed in the sponsor laboratory with advances in the fields of antisense oligonucleotide inhibitor design and computational RNA structure determination to study novel ways of inhibiting HIV by directly targeting the genome using two different mechanisms. In addition to studying basic mechanisms of retroviral inhibition at the laboratory bench, I will also learn about the disease from a bedside perspective by spending 10% of my effort engaged in a unique clinical training and research experience with HIV patients in drug-abusing and prison populations. My specific aims are to (1) inhibit HIV by inducing large-scale structural rearrangements in important regulatory domains in the HIV genome and (2) inhibit HIV reverse transcription by sterically blocking the enzyme using high-affinity antisense oligonucleotide analogs.