FBXO34 (F-box protein 34) is an E3 ubiquitin ligase located on chromosome 14 that plays a critical role in HIV-1 latency regulation. Primary function: FBXO34 promotes the ubiquitination and proteasomal degradation of heterogeneous nuclear ribonucleoprotein U (hnRNP U), an RNA-binding protein 1. Mechanism: hnRNP U normally interacts with the Rev region of HIV-1 mRNA through its amino-terminal domain (residues 1-339), thereby blocking HIV-1 translation and maintaining viral latency. FBXO34-mediated degradation of hnRNP U abolishes this inhibitory interaction, allowing HIV-1 gene expression and reactivation from latency 1. Disease relevance: The FBXO34/hnRNP U axis was identified through genome-wide CRISPR-Cas9 screening as a novel host factor associated with HIV-1 latent reservoir maintenance 1. Differential hnRNP U expression was detected between antiretroviral therapy-treated patients and healthy individuals, supporting clinical relevance 1. Clinical significance: This pathway represents a potential therapeutic target for HIV cure strategies, as modulating FBXO34 activity could enable controlled reactivation of latent HIV-1 for elimination. Additionally, FBXO34 was identified as a genetic locus (rs10140801) associated with COVID-19 severity in hospitalized patients 2, suggesting broader roles in viral pathogenesis.