# Defective viral genomes in RSV pathogenesis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $574,216

## Abstract

Summary
 Poor understanding of the mechanisms that modulate virus pathogenesis limits our ability to control
viral infections and reduce their public health burden. Non-standard viral genomes of the copy-back type
(cbVGs) that are generated during viral infections are the primary inducers of antiviral immunity to respiratory
syncytial virus (RSV) in vitro, in mice, and in humans. Most importantly, we recently reported that cbVGs
generated during RSV replication significantly impact the clinical outcome of infection in children and adults.
These data suggest that cbVGs are key determinants of viral pathogenesis and that their activity can be
harnessed to minimize viral-associated disease.
 It's clear that the virus host-interaction is complex, and it is essential to untangle this complexity to
identify better predictors of disease severity as well as better therapeutic strategies. A better understanding of
the factors that influence the generation and activity of cbVGs is necessary for exploiting them as a tool for
reducing the public health burden of RSV and related viruses. In studies funded in the original proposal, we
demonstrated that the presence of cbVG critically impact RSV pathogenesis. While detection of cbVGs soon
after infection is protective from severe disease, late or sustained presence of cbVGs associates with more
severe disease. Studies proposed here, directly follow these data and focus on investigating viral and host
factors that impact cbVG generation and activity. To do this, we will characterize the cbVG species present in
human respiratory secretions and we will study their function and association with distinct clinical outcomes.
This study will provide the first comprehensive investigation of naturally occurring cbVG species and will
identify unique features that determine their protective or potentially pathogenic functions (Aim 1). We will also
assess the impact of known RSV risk factors on cbVG generation to identify host determinants of cbVG
accumulation, and we will perform proof of concept experiments to test if cbVGs can be safely used to
minimize virus-induced disease in high-risk settings (Aim 2). Lastly, we will test the role of the host immune
bias in driving disease in patients with late or prolonged cbVGs and will identify potential targets for treatment
to reduce disease in these conditions (Aim 3).

## Key facts

- **NIH application ID:** 10808138
- **Project number:** 5R01AI137062-07
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Carolina B. Lopez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $574,216
- **Award type:** 5
- **Project period:** 2018-05-03 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10808138

## Citation

> US National Institutes of Health, RePORTER application 10808138, Defective viral genomes in RSV pathogenesis (5R01AI137062-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10808138. Licensed CC0.

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