LARP7 liquid-liquid phase separation restrains HIV replication

Abstract

Abstract HIV-1 initiates replication by hijacking host transcription factor P-TEFb through transactivator Tat. The majority of P-TEFb is kept inactive by 7sk snRNP until brought to transcription initiation complex by cellular or viral transactivators that dramatically accelerate transcription and enable full-length transcripts. Understanding the mechanism behind the release of P-TEFb from 7sk snRNP is key in blocking the initial step of HIV-1 replication. Here, we report that HIV-1 infection triggers liquid-liquid phase separation (LLPS) of LARP7, the core component of the 7sk snRNP, in T cells. We demonstrated that LARP7 is capable of forming condensates with Tat, and the conserved lysine residues in the intrinsically disordered region (IDR) of LARP7 are crucial for its phase separation and inhibition of Tat-mediated transcription. Our findings unravel a new mechanism that P-TEFb and Tat are retained in LARP7 condensates and HIV-1 transcription is restrained until accumulated Tat breaks the balance, which offer novel insights into the host protein's defense against HIV-1 infection through LLPS, highlighting the potential of targeting the phase separation of LARP7 as a new strategy for fighting HIV-1/AIDS.