Neurodevelopmental processes in the prefrontal cortex derailed by chronic HIV-1 viral protein exposure

Due to the widespread access to, and implementation of, combination antiretroviral therapy, individuals perinatally infected with human immunodeficiency virus type 1 (HIV-1) are living into adolescence and adulthood. Perinatally infected adolescents living with HIV-1 (pALHIV) are plagued by progressive, chronic neurocognitive impairments; the pathophysiological mechanisms underlying these deficits, however, remains understudied. A longitudinal experimental design from postnatal day (PD) 30 to PD 180 was utilized to establish the development of pyramidal neurons, and associated dendritic spines, from layers II-III of the medial prefrontal cortex (mPFC). Three putative neuroinflammatory markers (i.e., IL-1β, IL-6, and TNF-α) were evaluated early in development (i.e., PD 30) as a potential mechanism underlying synaptic dysfunction in the mPFC. Constitutive expression of HIV-1 viral proteins induced prominent neurodevelopmental alterations, independent of biological sex, in pyramidal neurons from layers II-III of the mPFC. Specifically, HIV-1 transgenic rats exhibited prominent deficits in dendritic and synaptic pruning, a developmental decrease in synaptic connectivity, and an age-related decline in synaptic efficacy. Examination of dendritic spine morphology revealed an age-related population shift towards a more immature dendritic spine phenotype in HIV-1 transgenic animals. There was no compelling evidence for neuroinflammation in the mPFC during early development. Understanding the neural mechanisms underlying chronic neurocognitive impairments in pALHIV may afford a key target for innovative therapeutics and cure strategies; an urgent need given the growing population of pALHIV.