PROGRAM SUMMARY The CHEETAH Center for the Structural Biology of HIV Infection, Restriction, and Viral Dynamics will be organized around: 1) three Scientific Projects that will advance our understanding of HIV-host interactions and provide the foundations for developing new therapeutic strategies for HIV treatment and cure, 2) three Scientific Cores that will advance important methodology and provide Center members with access to state-of-the-art technologies, 3) an Administrative Core that will coordinate Center activities and direct our Scientific Education, Public Outreach, and Molecular Animations, and 4) a Developmental Core that will engage and support the next generation of HIV structural biology researchers. Scientific Project 1 (Infecting the Cell) will define the steps in the first half of the HIV-1 life cycle in molecular and mechanistic detail. Scientific Project 2 (Innate Cellular Defenses Against HIV) will define the structural and mechanistic bases for host recognition, restriction, and innate immune responses to HIV-1. Scientific Project 3 (Multiscale Analysis and Modulation of Viral Dynamics) will characterize and modulate HIV-1 dynamics across multiple size and resolution scales; from whole-animal studies that will image and characterize sites of viral rebound at the cellular and tissue levels, to structural studies of proviral silencing and reactivation, to studies that attempt to create new pantropic blocks to enveloped virus budding and new biologics delivery systems. Scientific Core 1 (Tools for Biopolymer Synthesis and Screening) will develop new methodology and provide Center members with access to state-of-the-art instrumentation and expertise in Peptide Synthesis, Protein Design, and CRISPR Screening Methodology. Scientific Core 2 (Tools for Structural and Mechanistic Studies) will develop new methodology and provide Center members with access to state-of-the-art instrumentation and expertise in Fluorescence Spectroscopy and Dynamics, Scaffolds for Structure Determination, and Electron Cryotomography. Scientific Core 3 (Protein Production, Biophysical Characterization, and Structure Determination) will provide access to state-of-the-art instrumentation and expertise in Expression and Purification of Proteins and Complexes, Biophysical Characterization, and Structure Determination by both X-ray crystallography and cryoEM. Our Administrative Core will coordinate the entire range of Center activities; monitoring progress, and ensuring that all Personnel, Projects, and Cores are functioning effectively. This Core will also oversee Center Organization and Governance, and Scientific Education and Public Outreach, including our award-winning Science of HIV website and associated media. Our Developmental Core will administer our Collaborative Development, Seminar, Visiting Scholar, and Other Training Activities for early career investigators.