Our Center for the Structural Biology of Cellular Host Elements in Egress, Trafficking, and Assembly of HIV (CHEETAH) studies the structural biology of HIV-Host interactions involved in viral trafficking and assembly (as broadly defined). Our biological studies will focus on the structural biology, biochemistry, cell biology and molecular virology of five key aspects of the HIV-1 life cycle: 1) Reverse transcription and preintegration complex transformations and trafficking, 2) TRIM5a restriction, 3) Rev-dependent DEAD-box helicase transformations, 4) Virion assembly and budding, and 5) Virion structure, energetics and maturation. In each case, we aim to understand: 1) The molecular machines that drive these events, 2) The mechanisms by which host pathways are recruited and utilized, and 3) The underlying viral and cellular structures. In parallel, we will pursue technological developments in four different areas that will facilitate our biological studies and are important frontiers in HIV research: 1) Single-molecule analyses of native Rev complexes, 2) Multiscale computer simulations of viral capsid structure and assembly, 3) Advances in virus imaging, and 4) Development and application of methodology for imaging HIV in tissues. The efforts of our Center will also be extended through: 1) Extensive collaborations with other PSO Centers and colleagues, and access to scientific resources within the biomedical community, 2) A Collaborative Development Program that will fund promising collaborators who will enhance and benefit from interactions with our Center, and 3) Training programs for younger scientists. Our overall goals are to lay the groundwork for development of new antiviral strategies and to continue to develop HIV into an unparalleled model system for studying how a human virus interacts with its host.
Like other viruses, HIV-1 makes extensive use of host factors and pathways as it traffics through the cell and undergoes the transformations associated with each stage of the viral life cycle. These virus-host interfaces are, in principle, attractive targes for therapeutic intervention. Our program will inform efforts to develop this promise by providing a more comprehensive understanding of the structures, mechanisms, and functions of critical host-virus interactions.
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|Pastuzyn, Elissa D; Day, Cameron E; Kearns, Rachel B et al. (2018) The Neuronal Gene Arc Encodes a Repurposed Retrotransposon Gag Protein that Mediates Intercellular RNA Transfer. Cell 172:275-288.e18|
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|Bailey, Lucas J; Sheehy, Kimberly M; Dominik, Pawel K et al. (2018) Locking the Elbow: Improved Antibody Fab Fragments as Chaperones for Structure Determination. J Mol Biol 430:337-347|
|Pak, Alexander J; Voth, Gregory A (2018) Advances in coarse-grained modeling of macromolecular complexes. Curr Opin Struct Biol 52:119-126|
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|Larsen, Kevin P; Mathiharan, Yamuna Kalyani; Kappel, Kalli et al. (2018) Architecture of an HIV-1 reverse transcriptase initiation complex. Nature 557:118-122|
|Carter, Stephen D; Mageswaran, Shrawan K; Farino, Zachary J et al. (2018) Distinguishing signal from autofluorescence in cryogenic correlated light and electron microscopy of mammalian cells. J Struct Biol 201:15-25|
|Shepherd, Jason D (2018) Arc - An endogenous neuronal retrovirus? Semin Cell Dev Biol 77:73-78|
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