# Targeting Host Dependency Factors: A Paradigm Shift in Antiviral Strategy Against RNA Viruses

## TL;DR

This paper reviews a new approach to fighting RNA viruses by targeting host factors instead of the virus itself, which could lead to more effective and resistant-proof antiviral treatments.

## Contribution

The paper provides a systematic analysis of how RNA viruses exploit host dependency factors and advocates for a shift in antiviral strategy toward these conserved host targets.

## Key findings

- RNA viruses rely on host factors for entry, replication, and egress.
- Targeting host dependency factors offers a higher genetic barrier to resistance.
- HDF-targeting strategies show broad-spectrum potential across diverse RNA viruses.

## Abstract

RNA viruses, such as SARS-CoV-2 and influenza, pose a persistent threat to global public health. Their high mutation rates undermine the effectiveness of conventional direct-acting antivirals (DAAs) and facilitate drug resistance. As obligate intracellular parasites, RNA viruses rely extensively on host cellular machinery and metabolic pathways throughout their life cycle. This dependency has prompted a strategic shift in antiviral research—from targeting the mutable virus to targeting relatively conserved host dependency factors (HDFs). In this review, we systematically analyze how RNA viruses exploit HDFs at each stage of infection: utilizing host receptors for entry; remodeling endomembrane systems to establish replication organelles; hijacking transcriptional, translational, and metabolic systems for genome replication and protein synthesis; and co-opting trafficking and budding machinery for assembly and egress. By comparing strategies across diverse RNA viruses, we highlight the broad-spectrum potential of HDF-targeting approaches, which offer a higher genetic barrier to resistance, providing a rational framework for developing host-targeting antiviral therapies.