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CEST MRI Affirms HIV-1-Associated Neurometabolic Impairments in a Humanized Mouse Model
Gabriel C Gauthier1, Micah Summerlin1, Balasrinivasa R Sajja1
1University of Nebraska Medical Center.
Insights
Chemical exchange saturation transfer (CEST) MRI detects brain metabolic changes in human immunodeficiency virus 1 (HIV-1)-associated neurocognitive disorders (HAND). Antiretroviral therapy (ART) partially restores these metabolic alterations in a mouse model.
Area of Science:
- Neuroscience
- Biomedical Imaging
- Infectious Diseases
Background:
- Human immunodeficiency virus 1 (HIV-1)-associated neurocognitive disorders (HAND) persist despite antiretroviral therapy (ART), driven by neuroinflammation and metabolic dysfunction.
- Current methods for assessing HAND pathology are often invasive or lack specificity.
- There is a need for non-invasive imaging techniques to monitor disease progression and treatment response in HAND.
Purpose of the Study:
- To evaluate the utility of chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) for detecting HIV-1-induced neurometabolic impairments.
- To assess ART-mediated improvements in these metabolic alterations using CEST MRI in a humanized mouse model.
Main Methods:
- HIV-1-infected humanized mice underwent CEST MRI at baseline, post-infection, and after ART or vehicle treatment.
- CEST contrasts targeting creatine, glutamate, and nuclear Overhauser effect (NOE) were analyzed in multiple brain regions.
- Neuroinflammation and infection levels were confirmed via immunohistology and qPCR.
Main Results:
- HIV-1 infection led to significant reductions in cortical and hippocampal creatine and elevated NOE.
- Vehicle-treated infected mice showed decreased glutamate and creatine in several brain regions.
- ART treatment partially restored glutamate and creatine levels in specific brain regions, but did not affect NOE elevations.
Conclusions:
- CEST MRI effectively detects region-specific neurometabolic alterations associated with HIV-1 infection.
- CEST MRI demonstrates ART-mediated metabolic restorations in the brain, highlighting its potential as a non-invasive tool for monitoring HAND.
- This technique holds translational potential for assessing HAND pathology and therapeutic efficacy.
Purpose:
Human immunodeficiency virus 1 (HIV-1)-associated neurocognitive disorders (HAND) persist in people living with HIV-1 (PLWH) despite antiretroviral therapy (ART), driven by unresolved neuroinflammation and metabolic dysfunction. This study evaluates chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) detection of HIV-1-induced neurometabolic impairments and ART-mediated improvements in a humanized mouse model.
Methods:
HIV-1-infected CD34-NSG mice (n = 14) underwent CEST MRI to quantify metabolic profiles in the cortex, hippocampus, hypothalamus, piriform cortex, and thalamus at three timepoints: pre-infection (Week 0), 6 weeks-post-infection (WPI), and after 6 weeks of ART- or vehicle-treatment (12 WPI). CEST contrasts were analyzed at 2 ppm (creatine), 3 ppm (glutamate), and - 3.5 ppm (nuclear Overhauser effect, NOE). Neuroinflammation and infection were confirmed using immunohistology and qPCR.
Results:
At 6 WPI, HIV-1-infection reduced creatine in the cortex (p = 0.0006) and hippocampus (p = 0.01), and elevated NOE in the cortex (p = 0.001). At 12 WPI, vehicle-treated HIV-infected mice exhibited significantly decreased glutamate in the cortex (p = 0.004), hippocampus (p < 0.0001), and piriform cortex (p = 0.002); ART-treatment restored these levels in the cortex and hippocampus. Further, vehicle-treated mice exhibited decreased creatine in the cortex (p = 0.0002), hippocampus (p = 0.0003), piriform cortex (p = 0.0009), and thalamus (p = 0.006); ART-treatment restored these levels in the hippocampus, piriform cortex, and thalamus. Finally, vehicle-treated mice exhibited increased NOE in the cortex (p = 0.002) and thalamus (p = 0.003), but this was not restored by ART. CEST findings were supported by reductions in HIV-1 p24 + cells and neuroinflammatory markers in ART-treated brains.
Discussion:
CEST MRI detects region-specific HIV-1-induced neurometabolic alterations and ART-mediated restorations. This work establishes CEST MRI as a translational potential, non-invasive technique for monitoring HAND pathology and therapeutic efficacy.
