Abstract

Pestivirus bovine viral diarrhea virus (BVDV) is a major causative agent of bovine viral diarrhea-mucosal disease, responsible for substantial economic losses in the global cattle industry. BVDV employs sophisticated strategies to evade host antiviral innate immune responses; however, the precise mechanisms remain incompletely understood. In this study, we demonstrate that BVDV infection induces HIF-1α-mediated glycolytic reprogramming, which, in turn, antagonizes the RIG-I/MAVS pathway and suppresses type I interferon (IFN-I) production, thereby facilitating viral replication. We show that BVDV infection activates endoplasmic reticulum stress, leading to a marked increase in reactive oxygen species (ROS) that promote both the expression and stabilization of HIF-1α. As a key regulator of glycolysis, nuclear translocation of HIF-1α upregulates glycolysis-related proteins, including GLUT1, PFKP, HK2, and LDHA, thereby enhancing glycolytic flux. Furthermore, BVDV-induced glycolysis stimulates the formation of an HK2/MAVS/VDAC1 complex, which disrupts RIG-I–MAVS interaction and impairs pathway activation, inhibiting IFN-I production. Additionally, we found that lactate, a glycolytic byproduct, competitively binds to MAVS, impedes its mitochondrial localization, and consequently disrupts the engagement between RIG-I and MAVS. Collectively, our findings reveal a novel mechanism by which BVDV exploits the ROS−HIF-1α−glycolysis axis to attenuate MAVS-mediated antiviral signaling and promote viral replication.