Supplement for Ligand discovery for delineating cholesterol homeostasis in the brain

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Project Summary: HIV-1 is the causative agent of acquired immunodeficiency syndrome (AIDS), which is a multi-system disorder including the CNS. Neurological impairment affects approximately 60% of HIV-infected patients. HIV-1 enters the CNS at the early phase of infection, persists in that system for decades and induces multiple symptoms of motor, cognitive dysfunction and behavioral changes. Recently it has been estimated that nearly 30% of adults infected with HIV are affected. In the United States, HIV-1 infection is the most common cause of dementia in young adults. The more subtle forms of neurocognitive dysfunction however became more prevalent, leading to gradual, but ultimately significant functional deterioration of otherwise virologically controlled HIV+ patients. Among various factors, excitotoxic damage, neuroimmune dysfunction, lipid disorders and synaptic function are major factors in the HIV progression and aging process. Although all these remarkable discoveries have been made in the understanding of HIV-1 infection in the CNS at the molecular level via ex vivo (destructive) analysis, it cannot be directly applied to most brain tissues in vivo. Non-invasive PET neuroimaging approach can fill this void and provide direct and real-time correlation of aforementioned important signaling activity in the infected brain, facilitating novel HIV-1 neurotherapies. Therefore, we envision to directly monitor excitotoxicity (target: GluN2B-NMDA subtype), neuroinflammation (P2X7), cholesterol (CTP46A1) and synaptic (SV2A) function by PET as surrogate biomarkers in vivo in the brain of HIV-1 transgenic rat models. We speculate that longitudinal PET imaging of four distinct molecular imaging pathways will not only provide novel diagnostics to guide treatment strategies, but also study underlying mechanism of long-term HIV disease and aging, dysfunctional neuroimmune system as highlighted in the “Key NIH HIV Research Areas FY 2021-2025”.