CK1δ-Dependent SNAPIN Dysregulation Drives Lysosomal Failure in HIV-1 Vpr-Exposed Neurons: A Targetable Mechanism in HAND
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 (CK1{delta}) as a central mediator of this dysfunction, acting via phosphorylation of the adaptor protein SNAPIN. Vpr-induced CK1{delta} activation leads to hyperphosphorylation of SNAPIN, disrupting lysosomal positioning and motility. These defects are rescued by selective CK1{delta} inhibition, which restores lysosomal acidification, positioning, and mitophagy. Our findings define a novel Vpr-CK1{delta}-SNAPIN axis contributing to HAND and highlight lysosomal transport as a targetable mechanism in neurodegeneration.