Scaffold attachment factor B suppresses HIV-1 infection of CD4+ T cells by preventing binding of RNA polymerase II to HIV-1's long terminal repeat.

The 5' end of the HIV, type 1 (HIV-1) long terminal repeat (LTR) promoter plays an essential role in driving viral transcription and productive infection. Multiple host and viral factors regulate LTR activity and modulate HIV-1 latency. Manipulation of the HIV-1 LTR provides a potential therapeutic strategy for combating HIV-1 persistence. In this study, we identified an RNA/DNA-binding protein, scaffold attachment factor B (SAFB1), as a host cell factor that represses HIV-1 transcription. We found that SAFB1 bound to the HIV-1 5' LTR and significantly repressed 5' LTR-driven viral transcription and HIV-1 infection of CD4+ T cells. Mechanistically, SAFB1-mediated repression of HIV-1 transcription and infection was independent of its RNA- and DNA-binding capacities. Instead, by binding to phosphorylated RNA polymerase II, SAFB1 blocked its recruitment to the HIV-1 LTR. Of note, SAFB1-mediated repression of HIV-1 transcription from proviral DNA maintained HIV-1 latency in CD4+ T cells. In summary, our findings reveal that SAFB1 binds to the HIV-1 LTR and physically interacts with phosphorylated RNA polymerase II, repressing HIV-1 transcription initiation and elongation. Our findings improve our understanding of host modulation of HIV-1 transcription and latency and provide a new host cell target for improved anti-HIV-1 therapies.