# Essential early events in the flavivirus lifecycle

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $418,750

## Abstract

Project Summary
Arthropod-borne flaviviruses such as dengue virus, West Nile virus, yellow fever virus (YFV), and Zika
virus, are a major cause of human disease. We are studying the early, post-fusion and pre-replication
events in the flavivirus lifecycle by using the prototype flavivirus, YFV, as our model. Our overarching
hypothesis is that flaviviruses, which alternately replicate in vertebrate and invertebrate hosts, have
evolved to use i) highly conserved factors shared between hosts; and ii) multiple, redundant factors
that may not be well conserved between hosts. Therefore, discoveries made with YFV will be
validated and studied by comparison to other flaviviruses and between human and mosquito cells.
Aim 1 focuses on the post-fusion process of nucleocapsid uncoating, dissecting the mechanisms by
which cells unlock this fateful cargo. Aim 1 is a logical extension of our Preliminary Data showing that
the delivery of a translatable YFV genome requires cellular ubiquitylation and VCP/p97, a cellular
ATPase that extracts ubiquitylated proteins from large macromolecular complexes. Aim 2 focuses on
identifying the cellular protease(s) that cleave the viral NS1-2A polyprotein intermediate. Cleavage is
essential for flavivirus replication (shown here), yet the identity of this protease has remained elusive
for over two decades. We have identified a small family of related candidate NS1-2A proteases and
are validating their activity by rigorous, combinatorial genetic ablation. These efforts will solve long-
standing puzzles in flavivirus gene expression and replication and identify targets for future
development of broadly acting antivirals.

## Key facts

- **NIH application ID:** 10563191
- **Project number:** 5R01AI154844-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Pradeep D Uchil
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2021-03-09 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10563191

## Citation

> US National Institutes of Health, RePORTER application 10563191, Essential early events in the flavivirus lifecycle (5R01AI154844-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10563191. Licensed CC0.

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