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.

Grant Number: 1R21HD117691-01A1
NIH Institute/Center: NIH
Principal Investigator: Aditya Bade