The Center for HIV RNA Studies (CRNA) will focus on determining the structural and mechanistic bases of HIV-1 RNA dependent replication functions at the cellular, viral and atomic levels. Although considerable progress has been made over the past 25 years in understanding how proteins function in HIV-1 replication, comparatively little is known about how HIV-1 RNA structure, dynamics, trafficking, and interactions with proteins enable virus replication. Although HIV-1 RNA is exceptionally rich in biological functions, the paucity of detailed mechanistic insight into how these biological functions are executed is due to inherent difficulties in studying the structure and dynamics of RNA molecules. For example, it has been challenging to obtain high-resolution structural information for RNA and protein-RNA complexes using traditional X-ray crystallographic, NMR or cryo-electron microscopic approaches. It has also been difficult to study the functions and interactions of RNA molecules with proteins in vitro and in cells. The CRNA consists of a multidisciplinary team of structural biologists, chemists, cell and computational biologists, molecular biologists and virologists, many of whom are leaders in the study of HIV-1 RNA and the role of its structures in virus replication. They have developed and will further advance new approaches to overcome current technological obstacles, enabling mechanistic determination of the role of HIV-1 RNA structures and associated proteins in viral transcription, splicing, translation, packaging, particle assembly and interactions with restriction factors. The studies proposed herein will enable the CRNA to advance goals of clinical relevance, including the development of novel antiviral compounds, design of new strategies for the reactivation of latent proviruses, and the augmentation of host defenses against HIV infection. These studies will also result in the development of novel techniques that can be applied to all areas of RNA biology.

Public Health Relevance

Although much is known about how protein structures contribute to HIV-1 replication, little is known about the structures, dynamics and mechanistic roles played by viral RNA. Structural studies of RNAs are technically challenging, but are of key importance in understanding many biological processes, and could ultimately lead to the development of new approaches for the treatment of AIDS and many other human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM103297-03
Application #
8737284
Study Section
Special Emphasis Panel ()
Program Officer
Sakalian, Michael
Project Start
2012-09-17
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
3
Fiscal Year
2014
Total Cost
$4,278,491
Indirect Cost
$617,954
Name
University of Michigan Ann Arbor
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Ganser, Laura R; Lee, Janghyun; Rangadurai, Atul et al. (2018) High-performance virtual screening by targeting a high-resolution RNA dynamic ensemble. Nat Struct Mol Biol 25:425-434
Pham, Vincent V; Salguero, Carolina; Khan, Shamsun Nahar et al. (2018) HIV-1 Tat interactions with cellular 7SK and viral TAR RNAs identifies dual structural mimicry. Nat Commun 9:4266
Fritz, Matthew; Quinn, Caitlin M; Wang, Mingzhang et al. (2018) Determination of accurate backbone chemical shift tensors in microcrystalline proteins by integrating MAS NMR and QM/MM. Phys Chem Chem Phys 20:9543-9553
Zhang, Kaiming; Keane, Sarah C; Su, Zhaoming et al. (2018) Structure of the 30 kDa HIV-1 RNA Dimerization Signal by a Hybrid Cryo-EM, NMR, and Molecular Dynamics Approach. Structure 26:490-498.e3
Ge, Zhilei; Su, Zhaoming; Simmons, Chad R et al. (2018) Redox Engineering of Cytochrome c using DNA Nanostructure-Based Charged Encapsulation and Spatial Control. ACS Appl Mater Interfaces :
Bieniasz, Paul D; Kutluay, Sebla B (2018) CLIP-related methodologies and their application to retrovirology. Retrovirology 15:35
Kimsey, Isaac J; Szymanski, Eric S; Zahurancik, Walter J et al. (2018) Dynamic basis for dG•dT misincorporation via tautomerization and ionization. Nature 554:195-201
Nguyen, Hai; Case, David A; Rose, Alexander S (2018) NGLview-interactive molecular graphics for Jupyter notebooks. Bioinformatics 34:1241-1242
Johnson, Daniel S; Bleck, Marina; Simon, Sanford M (2018) Timing of ESCRT-III protein recruitment and membrane scission during HIV-1 assembly. Elife 7:
Bouchard, Jill J; Xia, Junchao; Case, David A et al. (2018) Enhanced Sampling of Interdomain Motion Using Map-Restrained Langevin Dynamics and NMR: Application to Pin1. J Mol Biol 430:2164-2180

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