ABSTRACT Thanks to the widespread availability of antiretroviral therapies (ART), children with vertically acquired HIV can survive and even thrive, but there remain concerns about the potential effects of long-standing ART usage particularly when initiated in children in whom a lifetime of treatment is anticipated. Among adults, metabolic side effects of protease inhibitors (PIs) including insulin resistance, hypertriglyceridemia and elevations in low density lipoprotein cholesterol are well-established. Whether PIs similarly induce this in children and whether there is resulting neurovascular compromise is unknown. In adults, vascular insufficiency is a risk factor for anxiety and depression. Neuropsychiatric adverse events (NP-AEs) such as anxiety and depression are not typically attributed to PI usage but such effects might be overshadowed in studies by the NP-AEs of efavirenz used in the same population. If PI-associated metabolic changes result in cerebrovascular insufficiency, this may be further compromising pre-existing endothelial injury in children mediated by the initial HIV CNS invasion and localized at autopsy to the basal ganglia and caudate regions. An inflammatory CNS milieu, even if transient, could further increase the risk of vascular pathology. We propose a model in which PI-induced metabolic changes result in CNS vasculopathy which contributes to the burden of psychiatric comorbidity in children with vertically acquired HIV as well as increasing their long-term risk of premature cerebrovascular disease. To evaluate our model, we will conduct an exposure-control study within a sub-set of Zambian children presently enrolled in an ongoing study of HIV-associated neurocognitive disorders. Children on a combined antiretroviral therapy (cART) regimen that includes a PI will be age-matched to children treated with a cART regimen that does not include a PI and comparisons will be made on metabolic profiles, noninvasive neurovascular imaging and NP-AEs including anxiety, depression and behavioral disorders.