# Structure and dynamics of RNA elements regulating viral aberrant RNA synthesis

> **NIH NIH DP2** · PRINCETON UNIVERSITY · 2022 · $1,412,295

## Abstract

SUMMARY
Seasonal influenza viruses cause >600 million cases annually and hundreds of billions of dollars
in losses. Pandemic and avian influenza viruses present an even greater threat because they can
dysregulate our immune response and/or spread to and shut down multiple organs. Current
evidence suggests that aberrant viral replication contributes to a dysregulating of the innate
immune response and the emergence of highly pathogenic strains from low pathogenic
precursors.
The transition from a low to highly pathogenic virus involves insertion of multiple basic amino
acids in the cleavage site of the viral hemagglutinin (HA) surface protein. In birds, this change in
HA allows the virus to spread systemically, resulting in mortality rates of up to 100% in poultry.
The molecular mechanism underlying insertion of amino acids in the cleavage site is not well
understood, but it may involve stuttering of the RNA polymerase in the HA gene, resulting in
nucleotide insertions.
The viral RNA polymerase can also delete nucleotides from the viral genome, resulting in shorter
aberrant RNAs. Recent studies have shown that pandemic and avian influenza A virus infections
produce RNA molecules of about 56-125 nucleotides in length, called mini viral RNAs, and that
their synthesis is correlated with the upregulation of disease markers. How the RNA polymerase
makes such large deletions in the viral genome is not known.
This project will use a novel method to stall the viral RNA polymerase during key steps of viral
replication and aberrant RNA synthesis, and use state-of-the-art biochemical, biophysical, and
structural approaches to reveal the steps of viral replication and genome encapsidation, as well
as aberrant RNA synthesis. In doing so, this project will contribute to a complete mechanistic
understanding of influenza replication and answer long-standing, fundamental questions about
the emergence of highly pathogenic influenza viruses.

## Key facts

- **NIH application ID:** 10472311
- **Project number:** 1DP2AI175474-01
- **Recipient organization:** PRINCETON UNIVERSITY
- **Principal Investigator:** Arend Jan te Velthuis
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,412,295
- **Award type:** 1
- **Project period:** 2022-09-08 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10472311

## Citation

> US National Institutes of Health, RePORTER application 10472311, Structure and dynamics of RNA elements regulating viral aberrant RNA synthesis (1DP2AI175474-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10472311. Licensed CC0.

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