Jiang Lin, Han Chunhua, Zhang Junshi, Li Guoqiang, Qiao Wentao, Tan Juan
Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China.
J Virol. 2025 Jul 22;99(7):e0016625. doi: 10.1128/jvi.00166-25. Epub 2025 Jun 3.
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.
原型泡沫病毒（PFV）是复杂的逆转录病毒，可在宿主中建立长期潜伏感染而不引起疾病，使其成为潜在的安全基因转移载体。了解参与PFV复制的宿主蛋白及其相互作用机制可能会提高基因转移效率。然而，已知只有少数细胞蛋白会影响PFV复制。在本研究中，对PFV感染的HT1080细胞进行转录组分析，发现可变电荷Y（VCY）mRNA显著下调，表明其在调节PFV复制中具有潜在意义。VCY的过表达显著抑制PFV复制，而敲低VCY则增强病毒复制，重新引入VCY蛋白可逆转这种情况。VCY与Tas DNA结合和转录激活结构域相互作用，并干扰其与PFV长末端重复序列和内部启动子的结合，从而抑制Tas的反式激活功能。VCY的N末端区域包含一个核定位信号，该功能对此至关重要。此外，VCY通过损害牛泡沫病毒（BFV）Tas的反式激活活性来抑制BFV复制，表明对FV复制具有广谱抑制作用。总体而言，我们的数据首次阐明了VCY通过转录干扰抑制PFV复制的作用，为病毒潜伏和宿主相互作用提供了有价值的见解。
重要性
泡沫病毒可整合到宿主染色体中，在天然宿主或实验感染动物中无致病性，使其成为安全有效的基因转移载体。它们在宿主中建立终身潜伏感染，无明显病理变化。迄今为止，仅鉴定出少数影响PFV复制的宿主因子。在本研究中，我们报告VCY通过调节转录激活因子Tas的功能来抑制PFV复制。目前，尚无研究探讨VCY与病毒之间的关系，这是关于其与病毒感染关联的首次报道。我们的数据为VCY在PFV生命周期中的作用提供了重要见解，这将有助于理解逆转录病毒潜伏感染的潜在机制。
