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.
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| Shepherd, Jason D (2018) Arc - An endogenous neuronal retrovirus? Semin Cell Dev Biol 77:73-78 |
| Coey, Aaron T; Larsen, Kevin P; Choi, Junhong et al. (2018) Dynamic Interplay of RNA and Protein in the Human Immunodeficiency Virus-1 Reverse Transcription Initiation Complex. J Mol Biol 430:5137-5150 |
| Swulius, Matthew T; Nguyen, Lam T; Ladinsky, Mark S et al. (2018) Structure of the fission yeast actomyosin ring during constriction. Proc Natl Acad Sci U S A 115:E1455-E1464 |
| Hammond, John A; Zhou, Li; Lamichhane, Rajan et al. (2018) A Survey of DDX21 Activity During Rev/RRE Complex Formation. J Mol Biol 430:537-553 |
| 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 |
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