Tracking myeloid heterogeneity in mouse models and cerebrospinal fluid of HIV-suppressed individuals to classify neuroinflammation and identify molecular markers associated with clinical pathology - PROJECT SUMMARY/ABSTRACT A major problem in virally suppressed people with human immunodeficiency virus (VS-PWH) is that despite well- controlled viral suppression many patients develop cognitive impairment, especially during aging. Furthermore, aging is a primary risk factor for cognitive impairment in the healthy population. Recent clinical and preclinical studies identified neuroinflammation increases during aging and in VS-PWH. For example, brain imaging studies in VS-PWH showed elevated markers for inflammation even under antiretroviral therapy. Moreover, the elevation of inflammation markers correlated with worse cognitive performance. Thus, the synergistic neuroinflammation brought on by aging and HIV may lead to the greater susceptibility for cognitive decline in some PWH. There is a lack of understanding for how neuroinflammation drives cognitive decline and a major unmet clinical need to develop a robust resource to track brain associated immune cells in VS-PWH to examine neuroinflammation more directly in living patients. This project aims to track inflammatory macrophage states in vivo using inflammatory mouse models for both aging and HIV infection (EcoHIV) and then determine which states are prominent in human disease and contribute to clinical pathology. The specific aims are to 1) determine the spatial distribution of microglia activation states in inflammatory mouse models. We will use hypothesis-driven spatial transcriptomics to map macrophage and microglia activation states in two mouse models with underlying neuroinflammation: two-year aged, and HIV infected (EcoHIV) mice. Second, we will isolate brain-associated immune cells in the cerebrospinal fluid (CSF) of VS-PWH to identify myeloid activation states which contribute to disease pathology. In aim 2a, we will identify gene expression modules in CSF-derived myeloid cells that associate with age and predict clinical pathology. Then in aim 2b, we will define the myeloid activation states enriched in CSF from VS-PWH compared to HIV-uninfected controls. The hypothesis is that genes enriched in CSF-derived myeloid cells will stratify patients with persistent neuroinflammation and at a greater susceptibility for cognitive impairment. Additionally, the spatial transcriptomics from the disease relevant animal models will provide a biologically relevant context for the disease-enriched activation states identified in VS-PWH. The overall goal of the proposed Career Development Award (K01) is to identify the cellular honing of immune cells to the brain, uncover disease modulating cellular markers of neuroinflammation on cognitive deficits, and establish CSF-derived cells as a unique resource for monitoring neuroinflammation in people living with HIV. These goals will be accomplished by the specific aims and facilitated by the proposed training plan which is divided into three domains: 1) biostatistics and data science, 2) inflammation in HIV and aging, and 3) professional development. The training plan was designed to gain expertise in HIV research, a new direction for the PI, and to establish an independent laboratory with a research program focused on the regulation of brain immune cell activity and the consequential impact on brain function in human disease.
