# Spring viraemia of carp virus modulates the time-dependent unfolded protein response to facilitate viral replication

## TL;DR

This study shows how a carp virus manipulates the host's unfolded protein response to boost its replication and suggests new ways to develop antiviral treatments.

## Contribution

The study reveals the time-dependent modulation of the UPR by SVCV and identifies novel antiviral targets.

## Key findings

- SVCV targets BiP and ATF4 early to enhance viral RNA synthesis and translation.
- Later UPR activation supports viral progeny release and immune responses.
- Modulating UPR pathways like ATF6 and PERK affects viral replication and offers therapeutic potential.

## Abstract

The spring viraemia of carp virus (SVCV) poses a significant threat to global aquaculture, yet effective antiviral drugs and vaccines remain unavailable. Understanding the interplay between host-pathogen interactions and SVCV replication is crucial for devising preventive strategies.

ZF4 cells were exposed to UV-inactivated SVCV or live SVCV at different multiplicities of infection, and the modulation of the unfolded protein response (UPR) was assayed by qPCR at different times. Moreover, ZF4 cells were treated with several UPR modulators to investigate their effect on viral replication. The UPR was also modulated in vivo in zebrafish larvae, and its impact on the survival against SVCV infection was evaluated.

This study reveals how SVCV exploits the host’s UPR to facilitate its replication. SVCV targets the immunoglobulin heavy chain-binding protein (BiP) and the activating transcription factor 4 (ATF4) during early infection to enhance viral RNA synthesis and translation. At later stages, activation of the BiP, the PKR-like ER kinase (PERK), and the inositol-requiring enzyme 1 alpha (IRE1α) pathways supports the release of viral progeny and induces cellular processes, including immune responses and apoptotic cell death. Furthermore, the data demonstrate that modulating UPR pathways, particularly ATF6 and PERK, significantly affect viral replication, providing a novel avenue for antiviral drug development. Preliminary in vivo studies suggest the feasibility of chemically modulating the UPR to combat SVCV, though optimizing administration conditions to maximize efficacy while minimizing side effects warrants further investigation. These findings offer critical insights into the molecular mechanisms underlying SVCV pathogenesis and highlight promising targets for therapeutic intervention.