Liquid-liquid phase separation of LARP7 restrains HIV-1 replication

Area of Science:

• Molecular Biology
• Virology
• Cell Biology

Background:

• Human immunodeficiency virus type 1 (HIV-1) replication relies on the transactivator Tat to hijack the host cell's positive transcription elongation factor b (P-TEFb).
• P-TEFb is typically kept inactive by the 7SK small nuclear ribonucleoprotein (snRNP) complex until recruited for transcription initiation.
• Viral and cellular transactivators facilitate P-TEFb recruitment, promoting viral RNA synthesis.

Purpose of the Study:

• To investigate the role of LARP7, a 7SK snRNP component, in HIV-1 replication.
• To elucidate the mechanism by which HIV-1 infection affects P-TEFb and LARP7 interactions.

Main Methods:

• Observation of HIV-1-induced liquid-liquid phase separation of LARP7.
• Analysis of Tat incorporation into LARP7 condensates.
• Mutation studies of conserved lysine residues in LARP7's intrinsically disordered region.

Main Results:

• HIV-1 infection triggers liquid-liquid phase separation of LARP7, forming distinct condensates.
• HIV-1 transactivator Tat is incorporated into these LARP7 condensates post-infection.
• Conserved lysine residues in LARP7 are crucial for its phase separation and for inhibiting Tat-mediated transcription.

Conclusions:

• HIV-1 infection induces LARP7 phase separation, creating a sequestration mechanism for P-TEFb and Tat.
• LARP7 condensates act as a barrier, restraining HIV-1 transcription by sequestering key regulatory factors.
• This highlights a novel regulatory pathway involving phase separation in controlling viral replication.