In Vivo Astrocyte Metabolism Using Acetate-2-13C MRS in HIV
Brian Schweinsburg, UC-San Diego
Biomedical and Clinical Sciences
Background: Human immunodeficiency virus (HIV) is associated with brain injury. Previous studies have demonstrated that HIV infection is related to reductions in brain volume, alterations in brain chemicals that are sensitive to cellular damage, and neurocognitive dysfunction. However, the underlying mechanisms of damage are not well understood, particularly in individuals living with HIV. In cellular models of HIV infection, it is hypothesized that alterations in certain neurotransmitter systems may be responsible for neural injury. One such system is the major excitatory neurotransmitter glutamate. HIV affects glutamate neurotransmission through a number of potential mechanisms. As an example, HIV may alter the release and recycling of this amino acid. Neurotransmitter glutamate is released by neurons and subsequently brought into neighboring cells called astrocytes where it is converted into glutamine. Astrocytes perform this vital function, in part, to "detoxify" glutamate before sending it back to the neuron. Excess glutamate surrounding neural cells can be toxic and can eventually result in neuronal death. This dysregulation is called glutamate-related excitotoxicity. While this is a likely mechanism of brain injury in HIV disease, no study has directly assessed the impact of HIV on glutamate/glutamine recycling in the living human brain.
Methods: Carbon-13 (13C) magnetic resonance spectroscopy permits in vivo measurements of this important metabolic process. To help track metabolism, a non-radioactive, 13C-labeled substrate is infused and the 13C label is passed through important metabolic cycles, including the glutamate/glutamine cycle, which reflects glutamate neurotransmission. The advantage of this technique is that one can non-invasively monitor the complete metabolism of the infused substrate, generating valuable metabolic information. In this study, 13C MR spectroscopy will be performed during an intravenous infusion of sodium-acetate-2-13C to study the effects of HIV on astrocyte metabolism. Eight HIV+ and 8 HIV seronegative healthy controls (HIV-) will be enrolled.
Expected Results: We predict that HIV+ participants will display increased rates of sodium acetate-2-13C label incorporation into C4-glutamate relative to healthy, HIV seronegative control participants (HIV-).This will reflect an increase in the astrocyte tricarboxylic acid (TCA) cycle rate, VtcaA. In addition, we predict that HIV+ participants will display decreased rates of sodium acetate-2-13C label incorporation into C4-glutamine relative to healthy, HIV seronegative control participants (HIV-).This will reflect a decrease in glutamate-glutamine cycling, Vcycle, with the result that less glutamate is recycled to glutamine, leading to potential excitotoxicity.
Conclusions and Future Directions: The project is innovative in that it will be the first to measure glutamate neurotransmission in individuals living with HIV. Our future objectives are to use this technique to characterize the mechanisms of HIV-related brain disease and monitor the effectiveness of antiretroviral therapy. The ability to monitor astrocyte metabolism and glutamate neurotransmission has particular relevance for identifying HIV-related neural mechanisms of damage and monitoring the outcome of treatment in the living brain where the ultimate goal is to improve the quality of life and reduce the healthcare burden of Californians living with HIV. Furthermore, by elucidating important aspects of the excitotoxic cascade, it may be possible to advance neuroprotective treatments.