Our Program on the Structural Biology of HIV Assembly, Budding, and Entry will focus on understanding and inhibiting the molecular interactions that allow HIV to assemble and bud from one cell and subsequently re- enter a new cell, thereby spreading infection. The Program is organized into five independent, but complementary, projects: 1) Structural Biology of HIV Budding (C.P. Hill, PI). This project will employ high throughput ?proteomics? and crystallographic approaches to define and determine the structures of cellular proteins and complexes involved in HIV-1 budding, including TsglO1 and proteins in the vacuolar protein sorting pathway. 2) Cryoelectron Tomography of HIV (G.J. Jensen, PI). Cryoelectron tomographic reconstructions of HIV virus-like particles will be determined at multiple stages of development, from initial budding to maturity. This work will capitalize on recent advances in electron microscopy to characterize the organization of HIV particles at near molecular resolution. 3) Inhibitors of HIV Assembly and Budding (W.I. Sundquist, PI). Structure-assisted development of inhibitors of HIV budding will be pursued using newly discovered inhibitors of the HIV-1 p6/Tsgl01 interaction and the three dimensional structure of this complex as a starting point. Inhibitors of HIV capsid assembly will also be pursued, starting with the development and implementation of high throughput screening protocols for discovering small molecule capsid assembly inhibitors. 4) Inhibition of HIV Entry and Envelope Folding (M.S. Kay, PI). This project will apply recent findings about the gp41- mediated viral fusion pathway to design and select inhibitors of viral entry and disrupt folding of the envelope protein. In summary, our Program will provide significant insights into how the HIV virion functions as a machine that can enter and exit cells, and how these processes can be inhibited.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM066521-05
Application #
7104906
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (50))
Program Officer
Basavappa, Ravi
Project Start
2002-08-15
Project End
2007-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
5
Fiscal Year
2006
Total Cost
$1,242,320
Indirect Cost
Name
University of Utah
Department
Biochemistry
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Bayro, Marvin J; Ganser-Pornillos, Barbie K; Zadrozny, Kaneil K et al. (2016) Helical Conformation in the CA-SP1 Junction of the Immature HIV-1 Lattice Determined from Solid-State NMR of Virus-like Particles. J Am Chem Soc 138:12029-32
Votteler, Jörg; Sundquist, Wesley I (2013) Virus budding and the ESCRT pathway. Cell Host Microbe 14:232-41
Gan, Lu; Jensen, Grant J (2012) Electron tomography of cells. Q Rev Biophys 45:27-56
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Briegel, Ariane; Chen, Songye; Koster, Abraham J et al. (2010) Correlated light and electron cryo-microscopy. Methods Enzymol 481:317-41
Chen, Songye; McDowall, Alasdair; Dobro, Megan J et al. (2010) Electron cryotomography of bacterial cells. J Vis Exp :
Rich, Rebecca L; Miles, Adam R; Gale, Bruce K et al. (2009) Detergent screening of a G-protein-coupled receptor using serial and array biosensor technologies. Anal Biochem 386:98-104
Kieffer, Collin; Skalicky, Jack J; Morita, Eiji et al. (2008) Two distinct modes of ESCRT-III recognition are required for VPS4 functions in lysosomal protein targeting and HIV-1 budding. Dev Cell 15:62-73
Kim, Sunghwan; Pang, Hong-Bo; Kay, Michael S (2008) Peptide mimic of the HIV envelope gp120-gp41 interface. J Mol Biol 376:786-97

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