Zinc finger protein 598 promotes HIV-1 replication and latent reactivation by stabilizing the expression of viral trans-activator of transcription Tat.

Human immunodeficiency virus type 1 (HIV-1) remains a severe global public health threat. As a key transcription activator, the HIV-1 Tat protein is essential for viral replication and latency establishment or reactivation. Therefore, to discover the key factors regulating Tat stability and the underlying mechanisms is helpful to provide the essential target for HIV-1 control. Here, we identify the E3 ubiquitin ligase Zinc Finger Protein (ZNF598) as a positive regulator of Tat stability, which reduces the K48-linked ubiquitination and prevents the proteasomal degradation of Tat. The regulatory effect of ZNF598 on Tat abundance is independent of its E3 ligase activity. Importantly, ZNF598 promotes HIV-1 replication and latent reactivation in HIV-1 target cells. Furthermore, ZNF598 knockdown enhances the inhibitory effectiveness of Tat inhibitors against HIV-1. ZNF598 also exerts similar effects across multiple HIV-1 strains with different tropisms and Tat variants, suggesting that ZNF598 could serve as a broad-spectrum antiviral target.