LAUSR

ABSTRACT The hypoxia signaling pathway controls hypoxia adaptation and tolerance of organisms, which is regulated by multiple mechanisms. Viral infection elicits various pathophysiological responses in the host. However, whether viral infection can affect the hypoxia response is not yet fully understood. In this study, we found that Spring viremia of carp virus (SVCV) infection in zebrafish caused symptoms similar to those in zebrafish under hypoxic conditions. Further assays indicated that SVCV infection activated the hypoxia signaling pathway in zebrafish. In addition, SVCV infection caused increased glycolysis and reactive oxygen species (ROS) levels in cells. Mechanistically, SVCV-G protein interacted with hif1α-a/b and attenuated their K48-linked polyubiquitination, leading to their stabilization and subsequent enhancement of target gene expression. Moreover, treatment with the HIF1α-specific inhibitor PX478 enhanced the antiviral ability against SVCV infection in zebrafish and zebrafish cells. This study reveals a relationship between SVCV infection and the hypoxia signaling pathway in fish and provides a strategy for reducing the damage of viral disease in the aquaculture industry. IMPORTANCE Viral infection triggers various pathophysiological responses in the host. The hypoxia signaling pathway controls hypoxia adaptation and tolerance of organisms. However, whether viral infection can affect the hypoxia response is not yet fully understood. This study showed that Spring viremia of carp virus (SVCV) infection activated the hypoxia signaling pathway and induced a hypoxia response. The SVCV-G protein interacted with hif1α-a/b and reduced their K48-linked polyubiquitination, leading to their stabilization and subsequent enhancement of target gene expression. Additionally, treatment with the HIF1α-specific inhibitor PX478 enhanced the antiviral ability against SVCV infection in zebrafish and zebrafish cells. Our findings not only reveal a relationship between SVCV infection and the hypoxia signaling pathway in fish but also provide a strategy for reducing the damage of viral disease in the aquaculture industry. Viral infection triggers various pathophysiological responses in the host. The hypoxia signaling pathway controls hypoxia adaptation and tolerance of organisms. However, whether viral infection can affect the hypoxia response is not yet fully understood. This study showed that Spring viremia of carp virus (SVCV) infection activated the hypoxia signaling pathway and induced a hypoxia response. The SVCV-G protein interacted with hif1α-a/b and reduced their K48-linked polyubiquitination, leading to their stabilization and subsequent enhancement of target gene expression. Additionally, treatment with the HIF1α-specific inhibitor PX478 enhanced the antiviral ability against SVCV infection in zebrafish and zebrafish cells. Our findings not only reveal a relationship between SVCV infection and the hypoxia signaling pathway in fish but also provide a strategy for reducing the damage of viral disease in the aquaculture industry.