CEST MRI assessment of HIV-1-associated neurometabolic impairments in a humanized mouse model.

Abstract

Objectives: Human immunodeficiency virus 1 (HIV-1)-associated neurocognitive disorders (HAND) persist despite antiretroviral therapy (ART), driven by ongoing neuroinflammation and metabolic dysfunction. This study assesses whether chemical exchange saturation transfer (CEST) MRI can detect HIV-1-induced neurometabolic impairments and ART-mediated improvements in a humanized mouse model.

Methods: HIV-1-infected CD34-NSG mice underwent CEST MRI at baseline (Week 0), 6 weeks post-infection (6 WPI), and after 6 weeks of ART or vehicle treatment (12 WPI). CEST contrast was quantified at 2 ppm (creatine-related), 3 ppm (glutamate-related), and -3.5 ppm (nuclear Overhauser effect, NOE). Neuroinflammation and infection were evaluated using immunohistochemistry and qPCR.

Results: At 6 WPI, HIV-1 infection reduced 2-ppm CEST contrast in the cortex and hippocampus and increased NOE in the cortex. By 12 WPI, vehicle-treated mice showed decreased 3-ppm contrast in the cortex, hippocampus, and piriform cortex, whereas ART restored contrast in the cortex and hippocampus. Vehicle-treated mice also showed reduced 2-ppm contrast in the cortex, hippocampus, piriform cortex, and thalamus; ART restored this in the hippocampus, piriform cortex, and thalamus. Increased NOE at -3.5 ppm was observed but did not show measurable improvement following ART. CEST alterations corresponded with decreased HIV-1 p24+ cells and reduced neuroinflammatory markers in ART-treated brains.

Conclusions: CEST MRI detects region-specific metabolic abnormalities during HIV-1 infection and region-specific metabolic recovery with ART, consistent with reduced viral burden and neuroinflammation. These findings support CEST MRI as a promising non-invasive biomarker for monitoring treatment response and disease progression in neuroHIV.