Synaptic Density and Neuroimmunologic Measures of HIV Neuropathogenesis During Antiretroviral Therapy

Widespread use of effective antiretroviral therapy (ART) in the past two decades has improved the clinical manifestations and altered the pathology of neurologic disease in people living with HIV (PLWH). However, in the context of this treatment that has successfully prolonged millions of lives, new pressing questions have emerged regarding the etiology of persistent neurological and cognitive impairment that frequently manifests in PLWH on ART. Our group at Yale recently developed and validated a novel positron-emission tomography (PET) radiotracer, [¹¹C]UCB-J, a ligand for the presynaptic vesicular membrane protein synaptic vesicular glycoprotein 2A (SV2A), to image synaptic density in the human brain. This project seeks to measure synaptic density longitudinally over 24 months in a larger group of PLWH on ART relative to a matched prospectively enrolled HIV-negative group. We will combine this breakthrough imaging methodology of synaptic density with PET imaging of neuroimmune status (using radioligand [¹¹C]PBR28 targeting the 18-kDa translocator protein, or TSPO, sensitive to microglia) to explore the premise that neuroimmune dysregulation during ART mediates reduced synaptic density. Finally, we aim to longitudinally integrate these measures with neurocognitive and laboratory assessments in parallel processing models that allow us to dissect mechanisms and clinical outcomes of HAND. This project will generate powerful clinical-translational support for potentially reversible brain alterations in synaptic density, and their relation to microglia levels and clinical and biological measures in PLWH. This program will set the stage for identification of therapeutic targets and provide a biomarker for interventional studies aimed to improve HIV-related injury in the CNS. This project is funded by R01MH123596 (PI: Spudich)