Immune dynamics shaping blood brain barrier integrity in virally suppressed people with HIV

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PROJECT SUMMARY/ABSTRACT Neuropsychiatric complications persist in people with HIV (PWH) despite suppressive antiretroviral therapy. Two common, often disabling conditions in PWH are cognitive impairment (CI) and major depressive disorder (MDD). However, the pathophysiology of central nervous system (CNS) dysfunction in PWH that results in these conditions remain elusive and thus a HIV high priority topic. The trafficking of activated peripheral blood mononuclear cells (PBMCs), specifically CD14+CD16+ monocytes, into brains of virally suppressed (VS)-PWH has emerged a putative contributor to neuroinflammation. We propose to test our hypothesis that VS-PWH will have blood brain barrier (BBB) disruption mechanistically linked to targeted, circulating soluble cytokines/chemokines and upregulation of PBMC surface proteins. The latter interact with tight junction and adherens junction proteins to weaken the BBB, promoting PBMC diapedesis into brain. BBB disruption may promote persistent neuroinflammation and altered neuronal activity contributing to neuropsychiatric sequela. To this end, we propose cross-sectional imaging and lumbar puncture to assess BBB integrity, with baseline and longitudinal neuropsychiatric assessments and blood sampling. 350 VS-PWH and 100 HIV-uninfected (HIV-) individuals will be recruited from the Johns G. Bartlett Clinic within the Johns Hopkins Hospital and in the surrounding Baltimore community. First, we aim to assess the effects of well-controlled HIV on the BBB and its contribution to neuropsychiatric conditions (Aim 1). We will assess BBB integrity using a novel, non-contrast magnetic resonance imaging technique that uses water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST), to determine BBB permeability to water, and thereby to small molecules. We have shown this to be sensitive to BBB change in mild cognitive impairment, a precursor to Alzheimer’s disease. Moreover, we have found WEPCAST to be well-tolerated and estimate PS values well in VS-PWH. Second, we aim to assess the relationship between circulating soluble markers, PBMC-associated markers, and BBB permeability to small molecules, which collectively may promote diapedesis into brain (Aim 2). We target factors implicated in a heightened transmigration of activated PBMCs across the BBB into brain, where they may contribute to neuronal damage and neuropsychiatric burden in VS-PWH. Finally, we aim to examine the relationship of activated PBMCs that transmigrate an intact BBB model to BBB permeability to small molecules (Aim 3). We innovate with the real-time assessment of ex vivo cellular function (BBB model) and in vivo BBB measures (WEPCAST). After 5 years of funding, this R01 will advance our understanding of BBB integrity and related PBMC migration into the brains of VS-PWH, which may contribute to neuroinflammation and related neuropsychiatric burden. These findings will inform next steps in the development of therapeutic approaches to minimize PBMC contribution to neuroinflammation in VS-PWH.