Abstract
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.