Project 5: HIV-1 genome stability and editing mediated by host proteins Summary In HIV-1 infected cells, many host proteins interact with viral RNA. These interactions can have positive or negative effects on viral replication. Some of these RNA protein interactions lead to editing of the genome, while others regulate RNA fate. CRNA investigators have discovered and characterized such several RNA:host protein interactions that form the basis for Project 5. This project will comprise a mix of structural and biological approaches to determine the precise nature and role of these important host protein-viral RNA interactions in HIV-1 replication.
In Aim 1 Bieniasz and Smith will determine the X-crystal structure of a novel dinucleotide- sensing RNA-destabilizing antiviral protein bound to its target. This protein appears to impose a major selective pressure that drives the biased nucleotide composition of the HIV-1 genome, and likely the genomes of many other viruses. Its discovery has far reaching implications for the understanding of the selective forces driving nucleotide composition of viruses and their hosts and the detection of non-self RNA.
For Aim 2, APOBEC3 proteins were shown by CRNA investigators to be incorporated into virions through interactions with viral RNA that appear to mimic the sequence preference of HIV-1 NC. Therefore, Bieniasz, Smith and collaborators will determine crystal structures of pigtail macaque and human APOBEC3H bound to an RNA target or a DNA substrate. Finally, Cullen has demonstrated that adenosine methylation at specific sites in the viral genome facilitates HIV-1 replication, and in Aim 3 of this project Cullen, Rouskin and Telesnitsky will determine the effect of m6A modification and m6A binding proteins on HIV-1 RNA structure and function, and their role in HIV- 1 replication.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
2U54GM103297-06
Application #
9408810
Study Section
Special Emphasis Panel (ZRG1)
Project Start
Project End
Budget Start
2017-09-15
Budget End
2018-08-31
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Hron, Tomáš; Farkašová, Helena; Gifford, Robert J et al. (2018) Remnants of an Ancient Deltaretrovirus in the Genomes of Horseshoe Bats (Rhinolophidae). Viruses 10:
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Krupovic, Mart; Blomberg, Jonas; Coffin, John M et al. (2018) Ortervirales: New Virus Order Unifying Five Families of Reverse-Transcribing Viruses. J Virol 92:
Blanco-Melo, Daniel; Gifford, Robert J; Bieniasz, Paul D (2018) Reconstruction of a replication-competent ancestral murine endogenous retrovirus-L. Retrovirology 15:34
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Kraus, Jodi; Gupta, Rupal; Yehl, Jenna et al. (2018) Chemical Shifts of the Carbohydrate Binding Domain of Galectin-3 from Magic Angle Spinning NMR and Hybrid Quantum Mechanics/Molecular Mechanics Calculations. J Phys Chem B 122:2931-2939
Marchant, Jan; Bax, Ad; Summers, Michael F (2018) Accurate Measurement of Residual Dipolar Couplings in Large RNAs by Variable Flip Angle NMR. J Am Chem Soc 140:6978-6983
Dick, Robert A; Zadrozny, Kaneil K; Xu, Chaoyi et al. (2018) Inositol phosphates are assembly co-factors for HIV-1. Nature 560:509-512

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