Brain Structural and Functional Connectome in HIV-Associated Neuroinflammation

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The parent grant RO1 MH118020 utilizes novel methodologies to assess the longitudinal changes in the trajectory of the brain structural and functional connectivity in people with HIV (PWH) compared to healthy controls (HC) in the context of intermediaries of inflammation and coagulopathy (soluble CD14 and CD163, D- dimer, soluble tissue factor and TF+ monocytes). Further, the parent grant also aims to assess the mediation effect of structural and functional connectivity and cerebral cortical thickness on specific cognitive domains. Preliminary data from the parent grant show that non-classical monocytes (NCMs) in PWH correlate with cognitive impairment. NCMs reach the highest levels in those with cerebral small vessel disease (CSVD) compared to no CSVD. Furthermore, monocyte TF expression is increased in PWH compared to HC. In this administrative supplement, we propose to extend our current investigations to study the effect of aging and HIV on non-classical monocyte subpopulations and TF expression in the context of CSVD, brain connectivity, and cognition. Our approach is to take advantage of the baseline clinical, imaging, and stored specimens of the 220 study participants enrolled to address the Specific Aims listed below: Aim 1: To assess the effect of aging and HIV on non-classical monocyte subtypes. We hypothesize that aging and HIV will have additive or synergistic effects on NCMs' cellular states characterized by pathways that release inflammatory factors and promote monocyte-endothelial cell interaction, an important step in monocyte transmigration to the brain parenchyma. NCMs subtypes will be assessed via Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq). The experiments will be conducted in PWH and healthy control study participants aged ≤40 and ≥50 without CSVD. Aim 2: To characterize the effect of cellular states of non-classical monocytes in CSVD. We hypothesize that PWH with CSVD will have unique subtypes of monocytes which will be assessed using CITE-seq and will be characterized using computational tools developed by our group and others. Specifically, CITE-seq will be performed on PWH and healthy control study participants aged ≥50, with and without CSVD. Aim 3: To assess whether cellular states of non-classical monocytes mediate alterations in brain connectivity and whether this is reflected in cognitive performance. We hypothesize that NCMs subtypes promote neuroinflammation, contributing to CSVD and altered brain connectivity. The clinical correlate of CSVD and altered brain connectivity is cognitive impairment. We will use our previously described PathCellNet approach along with Weighted Gene Correlation Network Analysis (WGCNA) optimized for single- cell analysis to define NCMs subtype-specific gene signatures that can be correlated with the clinical measurements. We will also use structural equation modeling (SEM) to understand the causal effect of NCMs on cognitive impairment.