Imaging Biomarker for Determining Antiretroviral-induced Neurodevelopmental Impairments

Project Summary Background: Children born to mothers with human immunodeficiency virus type-1 (HIV-1) infection are on the rise. With an increased coverage of antiretrovirals (ARVs) for pregnant women, especially in in resource-limited countries (RLCs), over one million ARV-exposed-HIV-1-uninfected (HEU) children are born every year. Even though ARVs have helped in preventing fetal HIV-1 infection and infection-associated maternal or fetal mortalities, risks of adverse events in fetuses linked to exposure to ARVs remain a major concern. Importantly effect of gestational ARVs exposure on pre- and post-natal neurodevelopment remain incompletely understood. These include physiological, metabolic, or functional harms to developmental brain of children who were born without chronic structural malformations. This is underscored by the reports of risk of postnatal neurodevelopmental deficits in HIV-1-exposed uninfected (HEU) children associated with, but not limited to, efavirenz (EFV), atazanavir (ATV), didanosine (ddI), or dolutegravir (DTG). Thus, with over a million HEU children born each year, and continuous efforts to develop new potent ARVs, development of a non-invasive bioimaging tool which can help for early-recognition (during gestation) of ARV-linked adverse neurodevelopmental outcomes is timely. Such bioimaging tool upon successful development will aid to define which ARVs have adverse effect on neurodevelopment, uncover altered molecular biomarkers as underlying mechanisms, irrespective of classification of ARVs or of administration through daily pills, long acting injectables or implants. Objective: (1) Implement novel chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) to non- invasively track ARVs-linked fetal neurodevelopmental adverse events during gestation in a rodent model. (2) Develop novel 3D variableRFCEST sequence which will acquire data from entire brain with varying RF saturation power that enables the simultaneous acquisition of various metabolites, mobile proteins or peptides in short duration. (3) Uncover altered fetal brain metabolites as an early-stage biomarkers for ARVs-associated developmental neurotoxicity. Our preliminary data: In preliminary work, sensitivity of CEST MRI to detect developmental neuronal impairment in mice embryo brain following ARV-exposure was determined. Hypothesis: We posit that CEST MRI can detect ART-linked fetal neuropathological biomarkers during pregnancy. Research Strategy: (a) Implement CEST MRI to determine the effect of EFV or DTG-based three drug regimens on neuronal membrane lipids and glutamate in developmental pre-frontal cortex in a rodent model. (b) Achieve rigor for CEST MRI sensitivity and specificity for molecular biomarkers. (c) Perform cross-validation of CEST MRI data with pharmacokinetics, metabolomics, and immunohistopathology data. Outcome: Successful implementation of CEST MRI to study fetal neurodevelopment will provide a non-invasive tool with sensitivity and specificity that has a potential to elucidate the underlying mechanisms of ART-induced developmental neurotoxicity.