An Empirical Mediation Analysis of Mechanisms Underlying HIV-1-Associated Neurocognitive Disorders

HIV-1-associated neurocognitive disorders (HAND), characterized by alterations in the core components of cognitive function and age-related disease progression, persist in the post-cART era. However, the neurobehavioral mechanisms that mediate alterations in the core components of cognitive function and the progression of neurocognitive impairments have yet to be systematically evaluated. To address this knowledge gap, statistical mediation analysis was assessed, providing a critical opportunity to empirically evaluate putative neurobehavioral mechanisms underlying HAND. Neurocognitive assessments, conducted in HIV-1 transgenic (Tg) and control animals across the functional lifespan (i.e., Postnatal Day (PD) 30 to PD 600), tapped multiple cognitive domains including preattentive processes, learning, sustained attention, and long-term episodic memory. Three longitudinal mediation models were utilized to assess whether deficits in preattentive processes mediate alterations in learning, sustained attention and/or long-term episodic memory over time. Preattentive processes partially mediated the relationship between genotype and learning, genotype and sustained attention, and genotype and long-term episodic memory across the functional lifespan, explaining between 44% and 58% of the HIV-1 transgene effect. Understanding the neurobehavioral mechanisms mediating alterations in HAND may provide key targets for the development of a diagnostic biomarker, novel therapeutics, and cure/restoration strategies.