Core 1 - Structural Biology Core

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Abstract – Core 1 – Structural Biology Core Approximately 40 million people worldwide are living with HIV/AIDS; however, a protective vaccine or functional cure remain elusive despite four decades of intense research. HIV-1 evades the immune system through its rapid structural evolution during infection and replication. The Duke Center for HIV Structural Biology will pursue structural studies of the evolution of the HIV-1 Envelope (Env) protein to elucidate structure-function mechanisms for viral entry, B-cell and T-cell activation, and viral rebound after antiretroviral therapy ART. The Structural Biology Core (Core 1) will support the overall mission of the Center by establishing a state-of-the-art pipeline for structural analysis of HIV-1 Env using a wide range of experimental techniques. The Core will provide access to cutting-edge techniques for structure determination and have a strong component of technology development that will ultimately advance our mechanistic understanding of Env. The research projects will benefit from having access to established protocols for structure determination as well as new methods resulting from the technology development efforts of the core. The Specific Aims of the Structural Biology Core are 1) to establish a high- throughput pipeline for routine characterization of the structure and dynamics of soluble HIV-1 trimers using high- resolution single-particle cryo-EM; 2) to develop advanced workflows for structural analysis of native HIV-1 samples imaged in-situ using cryo-electron tomography (ET) at near-atomic resolution; and 3) to establish structural methods for microsecond time resolution structural studies of HIV-1 Env. Completion of the three proposed aims will provide a solid infrastructure in structural biology needed to support the overall goals of the Center and its components. By providing access to state-of-the-art technology for the determination of structures of HIV-1 at the highest possible spatial and temporal resolution, will provide unique opportunities for visualizing key intermediates that could inform our understanding of HIV viral infection. The ability to determine high-resolution structures of soluble or native forms of Env will be critical to improve our understanding of HIV. The technologies developed as part of the Structural Biology Core will have implications beyond the field of HIV and would benefit structural studies of other biological systems. By making our tools available to the structural biology community, the activities of the core will have an even wider impact.