Brain metabolic imaging biomarkers of HIV-1 Infection During ART

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Project Summary/Abstract Our goal is to deploy novel magnetic resonance imaging (MRI) techniques to noninvasively track antiretroviral drugs (ARVs) in the CNS and measure virus-associated metabolites linked to neuropathological and neuroprotective outcomes resulting from ARVs. The MRI techniques employ a novel contrast coined as “chemical exchange saturation transfer (CEST)”. CEST is seen when an exchangeable proton of a biomolecule is magnetically saturated and transferred to water by chemical exchange causing signal reduction. Continuous exchange with bulk water protons leading to amplified signal reduction enables the detection of the signature biomolecule. CEST-based MRI provides specific detection of metabolites and greater sensitivity and spatial resolution compared to magnetic resonance spectroscopy (MRS). Indeed, our preliminary data demonstrate CEST MRI of myo-inositol and glutamate in mouse brains, which are a marker of glial activation, and a primary excitatory neurotransmitter, respectively. Employing the CEST contrasts of ARVs, we have successfully detected the drugs in the CNS using MRI. Based on these results, we posit neuropathological markers of altered myo- inositol and glutamate can be measured and linked to ART CNS biodistribution using noninvasive imaging techniques. The imaging techniques will be deployed in HIV-infected humanized mice including those animals enriched for human microglia. These animals are critical for preclinical studies to determine HIV-associated neuropathology and ART-linked neuroprotective activities. The imaging techniques can be translated to clinical research after optimization. Aim 1. Glutamate and myo-inositol will be measured using MRI employing their CEST contrasts in HIV-infected humanized microglial mice treated with combination ART (cART). We hypothesize that imaging results of glutamate and myo-inositol alterations reflect virus induced neuropathology as biomarkers of disease. The CEST contrasts of glutamate and myo-inositol will be first characterized in vitro followed by in vivo testing. There-dimensional (3D) CEST MRI sequences will be developed based on the in vitro results and used to measure the glutamate and myo-inositol simultaneously in the whole brain of HIV-infected humanized microglial mice treated with cART. Aim 2. ARV levels in the CNS will be measured using CEST MRI in infected mice. The results will be tested for association with metabolic imaging markers uncovered in aim 1 to study the effects of ART on neuropathological/neuroprotective outcomes. Viral, immune (CD4+ T cell) data will be acquired and compared with imaging results of metabolites and ART. The hypothesis is that the bioavailability/biodistribution of ARVs are associated with the mitigation of neuropathology. The overarching goal is to develop CEST as a reliable biomarker for measures of neuroHIV-1 pathology and ART neuroprotection. The project provides essential tools for preclinical studies of neuroHIV that can be translated for future human clinical research.