CK1δ-Dependent SNAPIN Dysregulation Drives Lysosomal Failure in HIV-1 Vpr–Exposed Neurons: A Targetable Mechanism in HAND

ABSTRACT HIV-associated neurocognitive disorders (HAND) persist in nearly 40% of virally suppressed individuals despite antiretroviral therapy (ART). Lysosomal dysfunction has emerged as a key contributor to HAND pathogenesis, yet the molecular mechanisms linking chronic HIV exposure to impaired neuronal degradation remain incompletely defined. Here, we identify HIV-1 Viral Protein R (Vpr) as a driver of lysosomal acidification failure, clustering, and degradative impairment in neurons. We uncovered casein kinase 1 delta (CK1δ) as a central mediator of this dysfunction, acting via phosphorylation of the adaptor protein SNAPIN. Vpr-induced CK1δ activation leads to hyperphosphorylation of SNAPIN, disrupting lysosomal positioning and motility. These defects are rescued by selective CK1δ inhibition, which restores lysosomal acidification, positioning, and mitophagy. Our findings define a novel Vpr–CK1δ–SNAPIN axis contributing to HAND and highlight lysosomal transport as a targetable mechanism in neurodegeneration. Graphical Abstract