Evaluating Changes to the Metabolic Profile of the Central Nervous System due to Active NeuroHIV Infection

Emory University, Atlanta GA

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Abstract

PROJECT SUMMARY/ABSTRACT Neurovirulent viral infections, such as human immunodeficiency virus-1 (HIV) result in a unique metabolic strain on the brain which contributes to the elevated indices of neurologic impairment observed in people living with HIV (PLWH). While the contributions of HIV infection and corresponding antiretroviral therapy (ART) on brain metabolism have been studied for small metabolites, including glucose and many amino acids, these methods are unable to detect larger metabolites including most lipids, which have the most diversity in the brain in comparison to other tissues. Lipid metabolism in the brain is altered by many stressors, including neurovirulent infection. Normally, the energy demands of the brain are overwhelmingly met by glucose. However, it has become evident that the brain can use more oxidizable substrates, such as FAs, than previously considered even under normal conditions. Elevated oxidation of radiolabeled FAs has been observed in HIV-infected cultured astrocytes. Additionally, tricarboxylic acid and FAO enzymes are increased in HIV-1 transgenic rodents. While these data indicate that HIV infection alters brain lipid metabolism, the full impact of HIV infection in the context of antiretroviral therapy (ART) and metabolic comorbidities on 1) brain lipid utilization and 2) the brain lipid metabolome remains uncharacterized. The goal of this project is to comprehensively characterize metabolic changes in the brain that occur due to HIV infection in the context of antiretroviral therapy (ART), under the duress of metabolic stressors, focusing primarily on lipids as they are largely unstudied. In Aim 1, I will determine the changes in brain lipid utilization following HIV infection. In Aim 2, I will Examine the contributions of HIV and ART to the brain metabolome after a period of metabolic duress. Both of these Aims will utilize brain tissue and primary cells derived from Eco-HIV/NL4-3GFP virus (EcoHIV) mice. These studies will expound upon my previous experience in brain lipid metabolism while gaining new knowledge in HIV pathogenesis, neuroinflammation, and ART pharmacology in the lab of Dr. Dionna Williams throughout my K00 phase. To further support my postdoctoral training, I will receive mentorship from my postdoctoral advisory committee comprised of leaders in the NeuroHIV field with expertise in astrocyte-neuron interactions, molecular mechanisms of neuroinflammation, and neurometabolism as well as biostatistics from multiple institutions. Mention postdoctoral advisory committee. Under the guidance of Dr. Williams, my postdoctoral advisory committee, and established mentors, advocates, and sponsors I have gained throughout my training, I will receive vital training in experimental design and methodology, scientific writing, and mentorship skills which will be complimented by networking and career development opportunities at regional, national and international scientific meetings and professional development workshops. Successful completion of the opportunities afforded by this K00 award will provide the necessary training and strong foundation for my development into a successful independent researcher and mentor.