The p400 complex promotes HIV-1 latency by suppressing viral transcription and altering the host cell state.

Eradicating HIV-1 is complicated by latently infected CD4+T cells harboring dormant proviruses capable of reactivation. Through a pooled shRNAmir screen targeting human chromatin regulators, we identified EP400, a member of the p400 chromatin remodeling complex, as a potent inhibitor of HIV-1 transcription in Jurkat and primary CD4+T cells. EP400 and its complex partner DMAP1 co-localize with paused RNA Polymerase II (RNAPII) at transcriptional start sites of protein-coding genes and their depletion modestly reduced RNAPII pausing. At the HIV-1 locus, EP400 and DMAP1 were co-recruited with RNAPII across the entire HIV-1 genome, and their depletion markedly increases RNAPII pause release. Together this suggests that EP400 may play a role in limiting HIV-1 transcriptional elongation. Additionally, EP400 depletion increased expression of key T-cell factors known to activate HIV-1 transcription. Therefore, the p400 complex reduces efficient HIV-1 transcriptional elongation and contributes to a CD4+T cell state unfavorable for HIV-1 transcription.