The study investigates the mechanism by which HIV-1 Tat protein activates nuclear factor κB (NF-κB) signaling to enhance viral transcription. Tat directly interacts with TRAF6, an essential upstream signaling molecule of the canonical NF-κB pathway, to increase TRAF6 oligomerization and auto-ubiquitination, leading to the synthesis of K63-linked polyubiquitin chains. This process further activates the NF-κB pathway and HIV-1 transcription. The interaction between Tat and TRAF6 is conserved among HIV-1, HIV-2, and SIV isolates, suggesting a common mechanism for HIV-1 subversion of host transcriptional pathways. The study also highlights the multifunctional roles of Tat in virus transcription and the importance of TRAF6 in HIV-1 infection.The study investigates the mechanism by which HIV-1 Tat protein activates nuclear factor κB (NF-κB) signaling to enhance viral transcription. Tat directly interacts with TRAF6, an essential upstream signaling molecule of the canonical NF-κB pathway, to increase TRAF6 oligomerization and auto-ubiquitination, leading to the synthesis of K63-linked polyubiquitin chains. This process further activates the NF-κB pathway and HIV-1 transcription. The interaction between Tat and TRAF6 is conserved among HIV-1, HIV-2, and SIV isolates, suggesting a common mechanism for HIV-1 subversion of host transcriptional pathways. The study also highlights the multifunctional roles of Tat in virus transcription and the importance of TRAF6 in HIV-1 infection.