Epigenetic silencing by the SMC5/6 complex mediates HIV-1 latency

Area of Science:

• Virology
• Epigenetics
• Molecular Biology

Background:

• Unintegrated HIV-1 proviruses are epigenetically silenced, but the mechanism remains unclear.
• Understanding HIV-1 latency is crucial for developing effective therapies.

Purpose of the Study:

• To identify host factors involved in the epigenetic silencing of unintegrated HIV-1.
• To elucidate the mechanism of HIV-1 latency establishment before integration.

Main Methods:

• Genome-wide CRISPR/Cas9 knockout screen to identify host factors.
• SUMOylation assays and inhibition studies.
• Analysis of HIV-1 DNA silencing, transcription, and replication.

Main Results:

• The host SMC5/6 complex was identified as essential for epigenetic silencing of unintegrated HIV-1.
• SMC5/6 binds to and SUMOylates unintegrated HIV-1 DNA.
• Inhibition of SMC5/6 SUMOylation prevents silencing, enables transcription, and rescues replication of integrase-deficient HIV-1.
• Blocking SMC5/6 or its SUMOylation activity suppresses HIV-1 latency establishment in T cells.

Conclusions:

• The SMC5/6 complex directly mediates HIV-1 latency establishment by epigenetically silencing proviruses before integration.
• Targeting SMC5/6 SUMOylation may offer a novel therapeutic strategy against HIV-1 latency.