Iron Dysregulation and Neuropsychiatric Complications of HIV Across the Lifespan: Impact of Biologic Factors, Antiretroviral Therapy and Genetics

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ABSTRACT People with HIV experience a much higher prevalence of depression and neurocognitive impairment (NCI) than the general population, and these disorders frequently co-occur, reducing medication adherence and quality of life and increasing mortality at least two-fold. Studies with large numbers of women as well as men are urgently needed to elucidate the neurobiologic mechanisms underlying these disorders as well as recently identified sex differences in vulnerability. Microglia-mediated neuro-inflammation and alterations in the Kynurenine Pathway (KP), which is essential for maintaining balanced mono-amine neurotransmitter (e.g., dopamine and serotonin) synthesis in the brain, are implicated in both disorders. Iron, dysregulated by HIV and combination antiretroviral therapy (cART), is intimately involved in microglial activation, the KP, and neurotransmitter metabolism. Our preliminary studies in a single neuro-HIV cohort and in HIV(-) persons indicate a significant role for dysregulated iron metabolism and iron-related gene networks in depression and NCI, as well as sex-specific effects. The proposed study leverages existing clinical, iron-biomarker, and genome-wide datasets from three large prospective HIV cohort studies to powerfully and comprehensively interrogate the role of iron in depression and NCI in both sexes. A combination of serum and cerebrospinal-fluid (CSF) biomarker, iron-centered genome-wide associations, and network bioinformatics approaches will be employed. Central hypotheses of this proposal are that iron dysregulation, and iron-related genes/networks, are major contributors to depression and NCI in PWH, with variability in overall risk explained in part by age, sex, HIV, and cART effects on iron. The Specific Aims are: 1) Determine the role of altered iron homeostasis in depression and NCI in PWH across the age spectrum and the proportion of susceptibility that is attributable to the effects of biologic factors, HIV, and cART on iron; 2) Identify novel iron-dependent pathways, iron-metabolic genes, and iron-quantitative trait loci associated with depression and NCI in women and men with HIV, and determine the extent to which these genetic effects are mediated via iron; 3) Explore the functional impact of network-prioritized iron-related gene knockdown on production of KP metabolites, using an in vitro HIV(+/-) human microglia model. In addition, Aim 1 will associate iron indices in a subset of individuals to CSF mono-amine metabolites. We expect these studies to advance understanding of mechanisms leading to depression and NCI in people with HIV, suggesting novel precision- medicine approaches to disease management and potentially impactful, iron- or KP-modulating interventions.