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
Liu, Chunmei; Janowski, Pawel A; Case, David A (2015) All-atom crystal simulations of DNA and RNA duplexes. Biochim Biophys Acta 1850:1059-71
Quek, Bao Lin; Beemon, Karen (2014) Retroviral strategy to stabilize viral RNA. Curr Opin Microbiol 18:78-82
Johnson, Daniel S; Toledo-Crow, Ricardo; Mattheyses, Alexa L et al. (2014) Polarization-controlled TIRFM with focal drift and spatial field intensity correction. Biophys J 106:1008-19
Ravera, Enrico; Salmon, Loïc; Fragai, Marco et al. (2014) Insights into domain-domain motions in proteins and RNA from solution NMR. Acc Chem Res 47:3118-26
Lamers, Susanna L; Fogel, Gary B; Nolan, David J et al. (2014) HIV-associated neuropathogenesis: a systems biology perspective for modeling and therapy. Biosystems 119:53-61
Johnson, Silas F; Collins, John T; D'Souza, Victoria M et al. (2014) Determinants of Moloney murine leukemia virus Gag-Pol and genomic RNA proportions. J Virol 88:7267-75
Alvarado, Luigi J; LeBlanc, Regan M; Longhini, Andrew P et al. (2014) Regio-selective chemical-enzymatic synthesis of pyrimidine nucleotides facilitates RNA structure and dynamics studies. Chembiochem 15:1573-7
Ganser, Laura R; Mustoe, Anthony M; Al-Hashimi, Hashim M (2014) An RNA tertiary switch by modifying how helices are tethered. Genome Biol 15:425
Rollins, Carrie; Levengood, Jeffrey D; Rife, Brittany D et al. (2014) Thermodynamic and phylogenetic insights into hnRNP A1 recognition of the HIV-1 exon splicing silencer 3 element. Biochemistry 53:2172-84
Giamba?u, George M; Luchko, Tyler; Herschlag, Daniel et al. (2014) Ion counting from explicit-solvent simulations and 3D-RISM. Biophys J 106:883-94

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