Brain structure and function and the CNS HIV reservoir in older people living with HIV - PROJECT SUMMARY / ABSTRACT People living with HIV (PWH) often exhibit a spectrum of cognitive, motor and mood symptoms, together referred to as HIV-associated neurocognitive impairment (HIV-NCI). HIV-NCI is estimated to affect over 40% of PWH and is more common as PWH age. HIV can enter the CNS within days of initial infection, and individuals with suppressed plasma viral loads might still have detectable HIV in their cerebrospinal fluid (CSF) for up to a decade, leading to inflammation within the CNS and subsequently HIV-NCI. Inflammation is believed to start very early in the disease process and precede overt clinical signs and symptoms of NCI. Identifying biomarkers of neuroinflammation related to presence of HIV virus in the CNS could help detect PWH who are now experiencing the neuroinflammatory effects of HIV. While incompletely understood, HIV-NCI is believed to be linked to chronic inflammatory processes in PWH, since immune responses may lead to both repair and damage in the CNS. Chronic inflammation may also contribute to changes in brain structure and altered connectivity. Our own prior work of 21 PWH ages≥50 shows that heightened segregation in the brain correlates with inflammatory biomarkers in PWH, while higher CSF NfL is related to higher markers of neuroinflammation or microglial activity. Our findings highlight the potential relationship between inflammation, neurodegeneration and functional connectivity (FC). Our overall goal in this proposal is to determine if the impacts of FC deficits, neuroinflammation, neurodegeneration or greater white matter hyperintensity (WMH) volume in HIV-NCI are mediated by CNS HIV viral persistence. We aim to (1) evaluate the specific contribution of HIV in the CNS to associations with inflammation, brain structure and function and cognition, and (2) examine whether detectable HIV RNA in the CSF mediates the associations between inflammation and neuronal injury, cerebrovascular disease and Alzheimer’s pathology in older PWH. Leveraging our team’s expertise in the fields of neuroHIV, biomedical imaging and virology, we leverage an existing research infrastructure and banked biospecimens from an existing cohort of older PWH at UNC. We will examine if the associations between fluid biomarkers of inflammation using next-generation proteomics and multimodal MRI markers of aging differ in PWH age≥50 with detectable vs. undetectable HIV RNA in CSF. We will also examine if the associations between biomarkers of inflammation and biomarkers of neuronal injury (NfL), cerebrovascular pathology (WMH volume) and AD pathology (NfL, phosphorylated tau217) are differentially impacted by presence of HIV within the CNS. The results of this study will provide an understanding of the mechanistic pathways by which viral presence in the CNS affects brain function and connectivity and neuroinflammation and provide potential future therapeutic targets to reduce the burden of HIV-NCI.
