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High-throughput interrogation of programmed ribosomal frameshifting in human cells
Martin Mikl1,2,3,4, Yitzhak Pilpel5, Eran Segal6,7
1Department of Computer Science and Applied Mathematics, Rehovot, 7610001, Israel. mmikl@gmx.at.
Nature Communications
|June 18, 2020
Summary
Scientists developed a high-throughput method to study programmed ribosomal frameshifting (PRF), a key viral replication process. This research uncovers new rules governing PRF and aids in developing antivirals targeting HIV and other viruses.
Area of Science:
- Molecular Biology
- Virology
- Computational Biology
Background:
- Programmed ribosomal frameshifting (PRF) is essential for the replication of many human viruses, including HIV and SARS-CoV.
- Understanding the mechanisms and regulation of PRF is crucial for developing antiviral strategies.
Purpose of the Study:
- To develop a high-throughput method for assessing sequence frameshifting potential.
- To systematically dissect the rules governing PRF and identify novel regulatory factors.
- To analyze natural variation in HIV gag-pol PRF rates and their clinical relevance.
Main Methods:
- Designed and tested over 12,000 sequences based on 15 viral and human PRF events.
- Assessed natural variation in HIV gag-pol PRF rates using over 500 clinical isolates.
- Developed computational models to predict PRF potential and rates.
Main Results:
- Discovered novel regulatory inputs for PRF based on amino acid properties and tRNA availability.
- Identified subtype-specific differences in HIV gag-pol PRF rates.
- Found associations between PRF rate optimality, viral load, and HIV subtypes.
- Computational models accurately predicted PRF potential and rates, including subtle HIV isolate differences.
Conclusions:
- The developed high-throughput approach systematically dissects PRF rules and identifies novel regulatory inputs.
- Analysis of clinical HIV isolates reveals subtype-specific PRF variations linked to viral load.
- Accurate predictive models for PRF offer potential for developing novel antiviral agents targeting PRF.
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