Gabriel C Gauthier, Micah Summerlin, Balasrinivasa R Sajja, Mariano G Uberti, Emma G Foster, Manjeet Kumar, Matthew Thiele, Santhi Gorantla, Aditya N Bade, Yutong Liu
{"title":"CEST MRI Affirms HIV-1-Associated Neurometabolic Impairments in a Humanized Mouse Model.","authors":"Gabriel C Gauthier, Micah Summerlin, Balasrinivasa R Sajja, Mariano G Uberti, Emma G Foster, Manjeet Kumar, Matthew Thiele, Santhi Gorantla, Aditya N Bade, Yutong Liu","doi":"10.21203/rs.3.rs-6821484/v1","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Discussion: </strong>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.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236917/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Research square","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.21203/rs.3.rs-6821484/v1","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
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.