CEST MRI Affirms HIV-1-Associated Neurometabolic Impairments in a Humanized Mouse Model.

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
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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.

CEST MRI证实人源化小鼠模型中hiv -1相关的神经代谢损伤。
尽管抗逆转录病毒治疗(ART),但人类免疫缺陷病毒1 (HIV-1)相关的神经认知障碍(HAND)在HIV-1 (PLWH)患者中仍然存在,这是由未解决的神经炎症和代谢功能障碍驱动的。本研究在人源化小鼠模型中评估化学交换饱和转移(CEST)磁共振成像(MRI)检测hiv -1诱导的神经代谢损伤和art介导的改善。方法对14只hiv -1感染的CD34-NSG小鼠进行CEST MRI,定量测定感染前(第0周)、感染后6周(WPI)和ART或载体治疗后6周(12 WPI)三个时间点皮质、海马、下丘脑、梨状皮质和丘脑的代谢谱。CEST对比在2 ppm(肌酸)、3 ppm(谷氨酸)和- 3.5 ppm(核Overhauser效应,NOE)下进行分析。采用免疫组织学和qPCR方法证实神经炎症和感染。结果在6 WPI时,hiv -1感染降低了皮质(p = 0.0006)和海马(p = 0.01)的肌酸,并升高了皮质的NOE (p = 0.001)。在12 WPI时,载药处理的hiv感染小鼠的皮层谷氨酸显著减少(p = 0.004),海马(p = 0.004)
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