This renewal application for the Center for HIV-1 RNA Studies (CRNA) focuses 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 30 years in understanding how proteins function in HIV-1 replication, comparatively little is known about how HIV-1 RNA structures, dynamics, trafficking, and interactions with proteins enable virus replication. The general paucity of high-resolution structural information for RNA and protein-RNA complexes reflects inherent challenges to using RNA as a subject for structural analysis and the inadequacy of traditional biophysical approaches to address these challenges. HIV-1 RNA is exceptionally rich in biologic functions, and progress in the CRNA?s first four years has begun to unlock structural and dynamic features of RNA elements in HIV-1 through the use of cutting edge technologies and incisive biologic approaches. The CRNA consists of a multidisciplinary team of structural biologists, chemists, cell and computational biologists, biochemists and virologists, many of whom are leaders in the study of HIV-1 RNA and the roles 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 host factors. These studies will enable the CRNA to advance goals of clinical relevance, including the development of novel classes of 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 powerful new techniques that can be applied to all areas of RNA biology.

Public Health Relevance

The molecular components of HIV-1, the virus that causes AIDS, include proteins and RNAs. Useful antiviral drugs that target HIV-1's proteins have been developed, but development of drugs that target RNAs have lagged far behind because RNA is technically challenging to work with. Recent decades of biomedical research have demonstrated that RNAs play critical roles in many diseases processes, including but by no means limited to AIDS, and thus structural understanding of RNA is a critical gap in the pipeline from basic biology to lifesaving cures for many diseases. The Center for HIV-1 RNA Studies (CRNA) is a multidisciplinary team of scientists who are combining their expertise to push the boundaries of RNA technology. Accomplishments from their first several years were pathbreaking both technically and in the biologic insight they provided about HIV-1 replication processes. These CRNA efforts have now set the stage for CRNA investigators to make major achievements of far-reaching biomedical significance through the proposed work. !

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
2U54GM103297-06
Application #
9408799
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sakalian, Michael
Project Start
2012-09-17
Project End
2022-08-31
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
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Hron, Tomáš; Farkašová, Helena; Gifford, Robert J et al. (2018) Remnants of an Ancient Deltaretrovirus in the Genomes of Horseshoe Bats (Rhinolophidae). Viruses 10:
Gaines, Christy R; Tkacik, Emre; Rivera-Oven, Amalia et al. (2018) HIV-1 Matrix Protein Interactions with tRNA: Implications for Membrane Targeting. J Mol Biol 430:2113-2127
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
LeBlanc, Regan M; Longhini, Andrew P; Tugarinov, Vitali et al. (2018) NMR probing of invisible excited states using selectively labeled RNAs. J Biomol NMR 71:165-172
Shi, Honglue; Clay, Mary C; Rangadurai, Atul et al. (2018) Atomic structures of excited state A-T Hoogsteen base pairs in duplex DNA by combining NMR relaxation dispersion, mutagenesis, and chemical shift calculations. J Biomol NMR 70:229-244
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
Patwardhan, Neeraj N; Cai, Zhengguo; Newson, Colby N et al. (2018) Fluorescent peptide displacement as a general assay for screening small molecule libraries against RNA. Org Biomol Chem :

Showing the most recent 10 out of 15 publications