The Role of DKK-1 in HIV-Associated Neurocognitive Disorder: A Clinically Relevant Therapeutic Target

Introduction: HIV-Associated Neurocognitive Disorder (HAND) remains a prevalent and debilitating complication in people living with HIV, even in the era of effective antiretroviral therapy. The condition not only compromises cognitive function but also significantly impairs quality of life, daily functioning, and treatment adherence. Increasing evidence implicates chronic neuroinflammation, neuronal injury, and dysregulation of signaling pathways including the Wnt/β-catenin pathway in HAND pathogenesis. Objection: This review explores the role of Dickkopf-related protein 1 (DKK-1), a potent endogenous inhibitor of the Wnt signaling pathway, in the context of HAND. DKK-1 has emerged as a critical modulator of neuroinflammatory processes and synaptic integrity. Discussion: Elevated DKK-1 expression has been associated with neuronal apoptosis, synaptic loss, and blood-brain barrier dysfunction hallmarks of HAND. The interplay between HIV proteins (e.g., gp120, Tat), host immune activation, and DKK-1 signaling may exacerbate neuronal damage. Importantly, preclinical studies suggest that inhibition of DKK-1 can restore neuroplasticity and reduce inflammation, offering a promising therapeutic strategy. Conclusion: DKK-1 contributes to HAND development by antagonizing the Wnt signaling pathway, leading to synaptic dysfunction and neuronal apoptosis. Modulation of DKK-1 and restoration of Wnt signaling represents a promising therapeutic approach for mitigating HIV-associated neurodegeneration. Nevertheless, further research is essential to clarify the precise molecular mechanisms by which DKK-1 contributes to HAND.