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The deubiquitinase USP8 has been reported to antagonize HIV-1 replication by reversing Vif-mediated ubiquitination of the host restriction factor A3G and shielding it from proteasomal degradation. Here, we identify an additional A3G-independent anti-HIV mechanism of USP8. In A3G-negative cells, USP8 exerts a potent inhibitory effect on HIV-1 replication by significantly suppressing viral transcription. Mechanistically, USP8 interacts with the HIV-1 trans-activator Tat through its C-terminal domain and mediates the removal of Tat\u2019s polyubiquitination chains in a manner dependent on USP8 catalytic activity. This disrupts the association between Tat and the HIV-1 LTR transactivation response (TAR) element, thus impairing Tat-mediated viral transactivation. Furthermore, given the essential role of Tat in driving viral gene expression, silencing of USP8 triggers latent HIV-1 reactivation. Collectively, our results, along with previous work, reveal that USP8 acts as a compelling anti-HIV factor that, by regulating both host and viral proteins, ultimately suppresses HIV-1 replication. These results deepen our understanding of USP8-mediated HIV-1 restriction and provide insights for the development of novel anti-HIV therapeutic strategies.<\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Ubiquitination modification contributes a non-negligible part to the regulation of HIV-1 replication, and the interpretation of key factors involved in this process has significantly benefited our understanding of the virus-host interplay. USP8 is a ubiquitin-specific protease that was recently identified to restrict HIV-1 replication by stabilizing the host restriction factor A3G through reversing the Vif-mediated ubiquitination of A3G. Here, we demonstrate an additional A3G-independent anti-HIV mechanism of USP8. In A3G-negative cells, USP8 directly interacts with and deubiquitinates Tat to cleave its K63-linked ubiquitination, thereby suppressing Tat-mediated HIV-1 trans-activation. The suppression of Tat-driven viral transcription induced by USP8 requires the enzymatic activity of USP8 and is effective in different HIV-1 tropic strains. In addition, the fact that Tat is a novel substrate of USP8 is validated both in cells and by\n                        <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                        deubiquitination assays. These findings illustrate the dual regulatory roles of USP8 on both host antiviral factors and viral proteins, expanding our understanding of host-mediated HIV-1 restriction.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.00598-26","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T13:00:41Z","timestamp":1790600441000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Deubiquitinase USP8 inhibits HIV-1 replication by suppressing Tat-mediated viral transactivation"],"prefix":"10.1128","volume":"100","author":[{"given":"Jinsong","family":"Yuan","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034haf133","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Infectious Diseases, Infectious Diseases and Pathogen Biology Center, The First Hospital of Jilin 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