This Project is designed to characterize the early post-entry steps of HIV-1 replication, core evolution, and TRIM5? restriction in structural and mechanistic detail. Following virus-cell fusion, the viral genomic RNA (gRNA) is reverse transcribed1-6, the core interacts with host factors and loses its capsid (?uncoating?)7-11, and the host restriction factor TRIM5? can recognize the capsid and block these transformations.12-16 To characterize these processes, we will determine 3D structures of replication initiation complexes that comprise reverse transcriptase (RT), the host tRNALys,3 primer, and various gRNA templates. We will study the conformational changes that accompany replication (Aim 1), develop and apply new single particle assays for studying reverse transcription within isolated viral cores (Aim 2), image transduced cells using fluorescent microscopy and correlated light and electron cryotomography (CLEM-ECT) to visualize and characterize core trafficking, reverse transcription, uncoating and restriction (Aim 3), and reconstitute, image and model TRIM5?- capsid complexes to learn how TRIM5? inactivates the core and stimulates innate immune responses (Aim 4).
| 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 |
| 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 |
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