FBXO34 promotes latent HIV-1 activation by post-transcriptional modulation

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Acquired immunodeficiency syndrome (AIDS) remains incurable due to persistent latent Human Immunodeficiency Virus type 1 (HIV-1) reservoirs.
• The molecular mechanisms governing HIV-1 latency are not fully understood, hindering effective eradication strategies.

Purpose of the Study:

• To identify novel host factors involved in the maintenance of HIV-1 latency.
• To elucidate the molecular mechanisms by which these factors regulate HIV-1 gene expression and latency.

Main Methods:

• Genome-wide CRISPR-Cas9 activation library screening to identify host factors.
• Affinity purification mass spectrometry to identify protein interactions.
• Cell-based assays in latent HIV-1 cell lines and primary CD4+ T lymphocytes.
• Analysis of hnRNP U expression in patient samples.

Main Results:

• FBXO34 (F-box protein 34) and hnRNP U (heterogeneous nuclear ribonucleoprotein U) were identified as key host factors in HIV-1 latent reservoir maintenance.
• FBXO34 promotes hnRNP U ubiquitination and degradation, disrupting hnRNP U's interaction with HIV-1 mRNA.
• hnRNP U binds to the ReV region of HIV-1 mRNA, inhibiting translation and promoting latency; its depletion or FBXO34 overexpression reactivates latent HIV-1.
• The FBXO34/hnRNP U axis was validated in primary CD4+ T cells, and altered hnRNP U expression was observed in patients on antiretroviral therapy (ART).

Conclusions:

• The FBXO34/hnRNP U axis represents a novel pathway regulating HIV-1 latency through ubiquitination and translational control.
• Targeting this axis offers a potential strategy for controlling latent HIV-1 reservoirs in patients.
• Understanding hnRNP U's role in HIV-1 latency provides critical insights for developing future HIV therapies.