VCY mediates inhibition of PFV replication via interaction with the transcription activator Tas.

Prototype foamy viruses (PFVs) are complex retroviruses that establish long-term latent infections in hosts without causing disease, positioning them as potential safe gene transfer vectors. Understanding the host proteins involved in PFV replication and their interaction mechanisms may enhance gene transfer efficiency. However, only a few cellular proteins are known to influence PFV replication. In this study, transcriptomic analysis of PFV-infected HT1080 cells revealed significant downregulation of variable charge Y (VCY) mRNA, indicating its potential significance in regulating PFV replication. Overexpression of VCY significantly inhibits PFV replication, whereas VCY knockdown enhances viral replication, which can be reversed by reintroducing the VCY protein. VCY interacted with the Tas DNA-binding and transcriptional activation domains and interfered with its binding to the PFV long terminal repeat and internal promoter, inhibiting the transactivation function of Tas. The N-terminal region of VCY, which contains a nuclear localization signal, is essential for this function. Additionally, VCY suppresses bovine foamy virus (BFV) replication by impairing the transactivation activity of BFV Tas, suggesting a broad-spectrum inhibitory effect on FV replication. Collectively, our data elucidate the role of VCY in inhibiting PFV replication through transcriptional interference for the first time, providing valuable insights into viral latency and host interactions.IMPORTANCEFVs can integrate into host chromosomes and are nonpathogenic in natural hosts or experimentally infected animals, making them safe and efficient gene transfer vectors. They establish lifelong latent infections without evident pathology in the host. To date, only a few host factors have been identified that affect PFV replication. In this study, we report that VCY inhibits PFV replication by modulating the function of the transcription activator Tas. Currently, there have been no studies examining the relationship between VCY and viruses, making this the inaugural report on its association with viral infection. Our data provide important insights into the role of VCY in PFV life cycle, which will aid in understanding the mechanisms underlying retroviral latent infection.