Pestivirus bovine viral diarrhea virus infection induces ROS-HIF-1a axis-driven glycolytic reprogramming, which increases viral replication by impairing RIG-I-dependent type I interferon response.

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. IMPORTANCE: Bovine viral diarrhea virus (BVDV), a member of the genus Pestivirus, is the causative agent of bovine viral diarrhea-mucosal disease, one of the most significant infectious diseases affecting cattle worldwide. BVDV employs diverse mechanisms to evade host innate antiviral immune response, while the precise processes remain incompletely understood. Here, we reveal that BVDV infection drives glycolytic reprogramming through the ROS-HIF-1α axis, leading to the formation of an HK2/MAVS/VDAC1 complex. This complex impairs the interaction between RIG-I and MAVS, resulting in suppressed IFN production. Moreover, we show that lactate, produced via LDHA-mediated glycolysis, binds to MAVS, inhibiting its mitochondrial localization and subsequent association with RIG-I. Together, these mechanisms reveal how BVDV harnesses glycolytic remodeling to dampen RIG-I/MAVS signaling and facilitate viral replication. Our study not only uncovers a potential therapeutic target for combating pestivirus infection but also provides valuable insights into immune evasion strategies shared within the Flaviviridae family, particularly among pestiviruses.