# Dissecting the viral and host constraints that govern influenza virus antigenic evolution

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2024 · $519,894

## Abstract

Abstract
Seasonal influenza A viruses (IAV) cause hundreds of thousands of deaths every year, despite widespread pre-
exposure and vaccination. IAV persists in the human population by continually evolving resistance to herd
immunity through a process known as antigenic drift. The evolutionary potential of RNA viruses like IAV is often
considered enormous due to their rapid replication and high mutation rates. In reality, the evolutionary potential
of IAV is highly constrained by the need to maintain a wide array of molecular functionality in a tiny genome. The
specific constraints limiting IAV evolution are very poorly characterized and defining them is critical for
understanding and potentially predicting the specific evolutionary pathways most likely to be taken by these
viruses. We discovered that phenotypic variation in the viral neuraminidase (NA) gene results in the viral
hemagglutinin (HA) gene taking divergent mutational pathways to escape neutralizing antibody pressure. These
data suggest that the need to maintain a functional balance between the opposing activities of the viral
glycoprotein genes (HA and NA) significantly constrains how the virus evolves to escape from host immune
pressure. We hypothesize that these viral constraints, along with additional constraints imposed by the host
environment, play significant roles in shaping the specific pathways of IAV antigenic evolution that occur in
humans. We will use a combination of in vitro and in vivo experimental evolution and mechanistic approaches to
define the specific host and viral factors that constrain the antigenic evolution of the HA gene. In Aim 1, we will
quantify phenotypic variation amongst recently circulating NA genes and quantify how this phenotypic variation
alters the evolutionary landscape of the HA gene. In Aim 2, we will explore how natural phenotypic variation in
NA influences antigenic escape in vitro and in vivo. Finally, in Aim 3, we will define how changes in the host
environment and sialic acid profile influence the potential for recent human seasonal H1N1 viruses to escape
from humoral immune pressure. Collectively, these studies will deepen our mechanistic understanding of the
antigenic evolution of seasonal influenza viruses in humans.

## Key facts

- **NIH application ID:** 10776965
- **Project number:** 1R01AI179910-01
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Christopher Byron Brooke
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $519,894
- **Award type:** 1
- **Project period:** 2023-12-01 → 2028-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10776965

## Citation

> US National Institutes of Health, RePORTER application 10776965, Dissecting the viral and host constraints that govern influenza virus antigenic evolution (1R01AI179910-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10776965. Licensed CC0.

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