Viral infection-induced CD97 upregulation facilitates viral invasion by interacting with viral proteins.

Virus-host interactions are crucial for regulating viral replication. While some interactions can suppress viral spread, others may promote it, and their underlying mechanisms remain poorly understood. Here, we report that infection with bovine herpesvirus 1 (BoHV-1) or bovine ephemeral fever virus (BEFV) upregulates the transcriptional expression of Cluster of Differentiation 97 (CD97). We identified the transcription factor Krüppel-like factor 4 (KLF4), which is elevated during BoHV-1, BEFV, or vesicular stomatitis virus (VSV) infection, as a key regulator of CD97 induction. Furthermore, CD97 was found to interact with BoHV-1-US4, BEFV-G1, and VSV-G, and to promote viral replication by enhancing viral adsorption and entry. These findings elucidate a previously unrecognized mechanism through which viruses exploit CD97 to facilitate host invasion, offering new insights into virus-host interactions.