Structural Basis of HIV-1 Rev Response Element and Rev Assembly

About This Grant

Abstract Human immunodeficiency virus (HIV) targets the immune cells and weakens our defense against many infections and cancer. Without treatment, HIV infection advances to acquired immunodeficiency syndrome (AIDS). Although combination antiretroviral therapy has dramatically improved clinical outcomes, the rapid development of drug-resistant HIV strains limits the selection of effective therapies available for patients. Thus, there is an urgent need to identify alternative viral targets for inhibition. An essential yet poorly understood step in HIV replication is the Rev-response element (RRE)-mediated nuclear export of viral RNAs. During HIV infection, partially spliced and unspliced viral RNAs need to be exported from the nucleus to the cytoplasm for viral protein synthesis and virion assembly. This process depends on a specific interaction between the viral protein Rev and RRE present in the incompletely spliced viral RNAs. Multimeric Rev proteins bind to the RRE structure and recruit the nuclear export complex for cytoplasmic translocation of the viral RNAs. Despite the essential function in HIV replication, the RRE-Rev complex is currently an unexploited target in HIV chemotherapy, largely due to the lack of the structural information on the full-length RRE. Using a tRNA-scaffold approach, we previously determined the crystal structure of RRE stem-loop II, the initial Rev protein binding site. In this proposal, we will (1) determine the structure of the full-length RRE, (2) test the sequential and cooperative mechanism of Rev assembly, and (3) develop antisense oligonucleotide and de novo protein inhibitors that disrupt RRE-Rev interaction. Since RRE-Rev interaction is absolutely required for viral RNA export and virion assembly, targeting this complex has strong potential to suppress HIV replication and reduce viral burden in HIV- 1 infected individuals.