Center for Infectious Disease Imaging, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., National Cancer Institute Campus at Frederick, Frederick, MD, USA.
J Neuroinflammation. 2018 Jul 14;15(1):207. doi: 10.1186/s12974-018-1244-z.
Although rates of severe HIV-associated neurocognitive disorders have declined in the post-antiretroviral treatment (ART) era, subtle deficits persist, possibly exacerbated by treatment non-adherence. The actual effects of ART interruption/initiation on brain glucose metabolism as a reflection of viral replication and neuroinflammation remain unclear. Our study investigates how treatment initiation and interruption alter brain glucose metabolism in SIV-infected macaques, using F-FDG PET in correlation with plasma and CSF viral loads (VL) and cytokine levels.
SIV-infected macaques (n = 7) underwent ART initiation only, ART interruption only, or both. Five uninfected animals served as controls. F-FDG PET imaging was performed at baseline and 1, 3, and 6 months after treatment modification. Mean and maximum standardized uptake values (SUV) for the whole-brain and subregions were calculated. Plasma and CSF VL and cytokine levels were measured. Paired t tests evaluated acute changes in whole-brain SUV from baseline to 1 month, while mixed-effect linear regression models evaluated changes over multiple timepoints and correlated SUV values with disease markers.
ART interruption was associated with increased SUVmean and SUVmax acutely, after 1 month (SUVmean 95% CI [0.044-0.786 g/ml], p = 0.037; SUVmax 95% CI [0.122-3.167 g/ml], p = 0.041). The correlation between SUV and time, however, was not significant when evaluated across all timepoints. Increased SUVmean and SUVmax correlated with decreased CD4+ and CD8+ T-cell counts and increased plasma VL. SUVmax was positively associated with increases in CSF VL, and there were borderline positive associations between SUVmax and IL-2, and between SUVmean and IL-15. The treatment initiation group showed no associations between imaging and disease biomarkers despite viral suppression, reduced cytokine levels, and increased CD4+ and CD8+ T-cell counts.
ART interruption is associated with increased brain glucose metabolism within 1 month of treatment cessation, which, in concert with increased levels of pro-inflammatory cytokines in the CSF, may reflect neuroinflammation in the setting of viral rebound. Although we cannot assert neurologic damage in association with cerebral hypermetabolism, it is a concerning outcome of ART non-adherence. Treatment initiation, meanwhile, did not result in significant changes in brain metabolism. HIV-induced neuroinflammation may require a longer period to abate than our follow-up period allowed.
尽管在抗逆转录病毒治疗（ART）时代后，严重的 HIV 相关神经认知障碍的发生率有所下降，但仍存在细微缺陷，治疗不依从可能会使这些缺陷恶化。ART 中断/启动对大脑葡萄糖代谢的实际影响，作为病毒复制和神经炎症的反映，目前尚不清楚。我们的研究使用 F-FDG PET 与血浆和 CSF 病毒载量（VL）和细胞因子水平相关联，调查了 SIV 感染的猕猴中治疗开始和中断如何改变大脑葡萄糖代谢。
SIV 感染的猕猴（n=7）仅接受 ART 启动，仅接受 ART 中断或两者兼有。5 只未感染的动物作为对照。在治疗改变后 1、3 和 6 个月进行 F-FDG PET 成像。计算整个大脑和亚区的平均和最大标准化摄取值（SUV）。测量血浆和 CSF VL 和细胞因子水平。配对 t 检验评估从基线到 1 个月时整个大脑 SUV 的急性变化，而混合效应线性回归模型评估多个时间点的变化，并将 SUV 值与疾病标志物相关联。
ART 中断后 1 个月，SUVmean 和 SUVmax 急性增加（SUVmean 95%CI [0.044-0.786 g/ml]，p=0.037；SUVmax 95%CI [0.122-3.167 g/ml]，p=0.041）。然而，当在所有时间点评估时，SUV 与时间之间的相关性并不显著。SUVmean 和 SUVmax 与 CD4+和 CD8+T 细胞计数的减少以及血浆 VL 的增加相关。SUVmax 与 CSF VL 的增加呈正相关，SUVmax 与 IL-2 之间以及 SUVmean 与 IL-15 之间存在边缘正相关。尽管病毒抑制、细胞因子水平降低以及 CD4+和 CD8+T 细胞计数增加，但影像学与疾病生物标志物之间无关联。
ART 中断与治疗停止后 1 个月内大脑葡萄糖代谢增加有关，这与 CSF 中促炎细胞因子水平升高一起，可能反映了病毒反弹时的神经炎症。虽然我们不能断言与大脑代谢过度相关的神经损伤，但这是 ART 不依从的一个令人担忧的结果。与此同时，治疗开始并没有导致大脑代谢的显著变化。HIV 引起的神经炎症可能需要比我们的随访时间更长的时间才能消退。
