This renewal application for the Center for HIV-1 RNA Studies (CRNA) focuses on determining the structural and mechanistic bases of HIV-1 RNA-dependent replication functions at the cellular, viral and atomic levels. Although considerable progress has been made over the past 30 years in understanding how proteins function in HIV-1 replication, comparatively little is known about how HIV-1 RNA structures, dynamics, trafficking, and interactions with proteins enable virus replication. The general paucity of high-resolution structural information for RNA and protein-RNA complexes reflects inherent challenges to using RNA as a subject for structural analysis and the inadequacy of traditional biophysical approaches to address these challenges. HIV-1 RNA is exceptionally rich in biologic functions, and progress in the CRNA?s first four years has begun to unlock structural and dynamic features of RNA elements in HIV-1 through the use of cutting edge technologies and incisive biologic approaches. The CRNA consists of a multidisciplinary team of structural biologists, chemists, cell and computational biologists, biochemists and virologists, many of whom are leaders in the study of HIV-1 RNA and the roles of its structures in virus replication. They have developed and will further advance new approaches to overcome current technological obstacles, enabling mechanistic determination of the role of HIV-1 RNA structures and associated proteins in viral transcription, splicing, translation, packaging, particle assembly, and interactions with host factors. These studies will enable the CRNA to advance goals of clinical relevance, including the development of novel classes of antiviral compounds, design of new strategies for the reactivation of latent proviruses, and the augmentation of host defenses against HIV infection. These studies will also result in the development of powerful new techniques that can be applied to all areas of RNA biology.
The molecular components of HIV-1, the virus that causes AIDS, include proteins and RNAs. Useful antiviral drugs that target HIV-1's proteins have been developed, but development of drugs that target RNAs have lagged far behind because RNA is technically challenging to work with. Recent decades of biomedical research have demonstrated that RNAs play critical roles in many diseases processes, including but by no means limited to AIDS, and thus structural understanding of RNA is a critical gap in the pipeline from basic biology to lifesaving cures for many diseases. The Center for HIV-1 RNA Studies (CRNA) is a multidisciplinary team of scientists who are combining their expertise to push the boundaries of RNA technology. Accomplishments from their first several years were pathbreaking both technically and in the biologic insight they provided about HIV-1 replication processes. These CRNA efforts have now set the stage for CRNA investigators to make major achievements of far-reaching biomedical significance through the proposed work. !
