Abstract
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, remain 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) in HIV-1 transgenic (Tg) and control animals. 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 and progressive synaptodendritic dysfunction, independent of biological sex, in pyramidal neurons from layers II-III of the mPFC. From a neurodevelopmental perspective, HIV-1 Tg rats exhibited prominent deficits in dendritic and synaptic pruning. With regards to progressive synaptodendritic dysfunction, HIV-1 Tg animals exhibited an age-related population shift towards dendritic spines with decreased volume, increased backbone length, and decreased head diameter; parameters associated with a more immature dendritic spine phenotype. There was no compelling evidence for neuroinflammation in the mPFC during early development. Collectively, progressive neuronal and dendritic spine dysmorphology herald synaptodendritic dysfunction as a key neural mechanism underlying chronic neurocognitive impairments in pALHIV.
Highlights
Reports of children diagnosed with acquired immune deficiency syndrome (AIDS)occurred early in the pandemic [1,2]
The epidemiological features of pediatric human immunodeficiency virus type 1 (HIV-1) have shifted, resulting in a growing population of perinatally infected adolescents living with HIV-1
Despite the disproportionate number of adolescents affected by HIV-1 worldwide, neurodevelopmental outcomes of perinatally infected adolescents living with HIV-1 (pALHIV) remain understudied [7]
Summary
Reports of children diagnosed with acquired immune deficiency syndrome (AIDS). Occurred early in the pandemic [1,2]. The disease was associated with high mortality rates [3]. With widespread access to, and implementation of, combination antiretroviral therapy (cART), pediatric human immunodeficiency virus type 1 (HIV-1). Evolved from a fatal disease to a chronic disease (e.g., [4,5]). The epidemiological features of pediatric HIV-1 have shifted, resulting in a growing population of perinatally infected adolescents living with HIV-1 (pALHIV). Approximately 2.78 million children and adolescents (0–19 years of age) are living with either perinatally or horizontally acquired HIV-1 [6]. Despite the disproportionate number of adolescents affected by HIV-1 worldwide, neurodevelopmental outcomes of pALHIV remain understudied [7]
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