Abstract

This Project is designed to elucidate the mechanistic bases for HIV-1 budding and its inhibition by the host factor retroCHMP3. To initiate budding, HIV-1 Gag binds ESCRT-I1-4 and ALIX5-7, two early-acting factors in the host Endosomal Sorting Complexes Required for Transport (ESCRT) pathway. These factors, in turn, recruit the late-acting ESCRT factors CHMP2, CHMP4 (ESCRT-III) and VPS4 (AAA ATPase)2,8-10 (reviewed in refs. 11-16). Numerous models for membrane constriction and fission have been proposed.17-26 We favor those in which: 1) ESCRT-III proteins form spiraling filaments that recruit VPS4 and constrict the membrane neck from the cytoplasmic face and 2) The VPS4 ATPase promotes lipid mixing by remodeling the underlying ESCRT-III scaffold. We now propose to determine the structural bases for membrane remodeling by ESCRT-III filaments and VPS4 (Aims 1 and 2), characterize how mammalian retroCHMP3 (ESCRT-III) proteins can inhibit HIV budding without inducing cellular toxicity (Aim 3), and image ESCRT assemblies within budding virions by electron cryotomography (Aim 4). These studies will reveal how HIV-1 uses the host ESCRT-III/VPS4 machinery to exit cells and how host retroCHMP3 proteins can specifically inhibit this process.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM082545-12
Application #
9564939
Study Section
Special Emphasis Panel (ZRG1)
Project Start
Project End
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
12
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
University of Utah
Department
Type
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112

  Publications

Wang, Haoqing; Barnes, Christopher O; Yang, Zhi et al. (2018) Partially Open HIV-1 Envelope Structures Exhibit Conformational Changes Relevant for Coreceptor Binding and Fusion. Cell Host Microbe 24:579-592.e4
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
Wagner, Jonathan M; Christensen, Devin E; Bhattacharya, Akash et al. (2018) General Model for Retroviral Capsid Pattern Recognition by TRIM5 Proteins. J Virol 92:
Donaldson, G P; Ladinsky, M S; Yu, K B et al. (2018) Gut microbiota utilize immunoglobulin A for mucosal colonization. Science 360:795-800
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
Redman, Joseph S; Francis, J Nicholas; Marquardt, Robert et al. (2018) Pharmacokinetic and Chemical Synthesis Optimization of a Potent d-Peptide HIV Entry Inhibitor Suitable for Extended-Release Delivery. Mol Pharm 15:1169-1179
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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