The hepatitis E virus (HEV) is a leading cause of acute hepatitis worldwide. HEV infection can become chronic in immunocompromised individuals, in whom virus–host recombinant variants (VHRVs) can be detected. These variants often harbor host-derived insertions in the polyproline rich region (PPR) and most display enhanced replication in vitro. However, the mechanisms underlying this replicative advantage remain unclear. It is likely that genes of the infected cells are differentially expressed according to the replicative capacity of the strain. The host factors involved in the improvement of the replicative capacity of these VHRVs are yet to be identified.

In this study, we analyzed the host transcriptional response to 7 VHRVs in HepG2/C3A cells using bulk RNA sequencing at 48 h and 168 h post-infection. Five VHRVs (RNF19A, ZNF787, KIF1B, RPS17, and EEF1A1) previously associated with a high replication rate induced more significant distinct transcriptomic changes than low-replicative variants (RNA18 and RPL6), particularly at 168 h post-infection. A shared set of 25 genes, especially interferon-stimulated genes (ISGs), was upregulated in cells infected with high-replicating variants. Interestingly, ISG induction was limited at 48 h post-infection despite high viral RNA concentrations, suggesting a delayed antiviral response. At 168 h post-infection, high ISG expression coincided with high viral loads, indicating that VHRVs may evade or exploit immune defenses. Our findings reveal candidate ISGs such as IFIT1 and ISG15 that may influence HEV persistence and immune escape. These results offer new insights into the interplay between VHRV replication and host immunity.