Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute.
Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts.
AIDS. 2019 Mar 15;33(4):615-625. doi: 10.1097/QAD.0000000000002121.
The relationship of cerebrospinal fluid (CSF) extracellular vesicles to neurocognitive impairment (NCI) in HIV-infected individuals is unclear. Here, we characterize CSF extracellular vesicles and their association with central nervous system (CNS) injury related biomarkers [neurofilament light (NFL), S100B, neopterin] and NCI in HIV-positive individuals on combination antiretroviral therapy (cART).
A cross-sectional and longitudinal study of CSF samples from HIV-positive individuals on cART.
NFL, S100B and neopterin were measured by ELISA in 190 CSF samples from 112 individuals (67 HIV-positive and 45 HIV-negative). CSF extracellular vesicles were isolated and characterized by electron microscopy, nanoparticle tracking analysis, immunoblotting for exosome markers (CD9, CD63, CD81, FLOT-1) and ELISA for HLA-DR.
HIV-positive individuals had median age 52 years, 67% with suppressed plasma viral load (< 50 copies/ml), median CD4 nadir 66 cells/μl and CD4 cell count 313 cells/μl. CSF NFL, S100B and neopterin levels were higher in HIV-positive vs. HIV-negative individuals, and nonsuppressed vs. suppressed HIV-positive individuals. Although CSF NFL and S100B levels were higher in NCI vs. unimpaired HIV-positive individuals (P < 0.05), only NFL was associated with NCI in adjusted models (P < 0.05). CSF extracellular vesicles were increased in HIV-positive vs. HIV-negative individuals, and NCI vs. unimpaired HIV-positive individuals (P < 0.05), and correlated positively with NFL (P < 0.001). HLA-DR was enriched in CSF extracellular vesicles from HIV-positive individuals with NCI (P < 0.05), suggesting that myeloid cells are a potential source of CSF extracellular vesicles during HIV infection.
Increased CSF extracellular vesicles correlate with neuronal injury biomarker NFL in cART-treated HIV-positive individuals with neurocognitive impairment, suggesting potential applications as novel biomarkers of CNS injury.
脑脊液（CSF）细胞外囊泡与 HIV 感染者神经认知障碍（NCI）的关系尚不清楚。在此，我们描述了 HIV 阳性个体接受联合抗逆转录病毒治疗（cART）时 CSF 细胞外囊泡的特征，及其与中枢神经系统（CNS）损伤相关生物标志物[神经丝轻链（NFL）、S100B、新蝶呤]和 NCI 的关系。
cART 治疗的 HIV 阳性个体的 CSF 样本的横断面和纵向研究。
通过 ELISA 法检测 112 名个体（67 名 HIV 阳性和 45 名 HIV 阴性）的 190 份 CSF 样本中的 NFL、S100B 和新蝶呤。通过电子显微镜、纳米颗粒跟踪分析、外泌体标志物（CD9、CD63、CD81、FLOT-1）的免疫印迹法和 HLA-DR 的 ELISA 法分离和表征 CSF 细胞外囊泡。
HIV 阳性个体的中位年龄为 52 岁，67%的个体病毒载量得到抑制（<50 拷贝/ml），CD4 细胞计数的中位值为 66 个/μl，CD4 细胞计数为 313 个/μl。与 HIV 阴性个体相比，HIV 阳性个体的 CSF NFL、S100B 和新蝶呤水平更高，且未抑制 HIV 阳性个体的水平高于抑制 HIV 阳性个体。尽管 NCI 患者的 CSF NFL 和 S100B 水平高于无认知障碍的 HIV 阳性个体（P<0.05），但在调整后的模型中，仅 NFL 与 NCI 相关（P<0.05）。与 HIV 阴性个体相比，NCI 患者的 CSF 细胞外囊泡水平更高（P<0.05），与无认知障碍的 HIV 阳性个体相比，NCI 患者的 CSF 细胞外囊泡水平更高（P<0.05），且与 NFL 呈正相关（P<0.001）。HLA-DR 在外泌体中富集在 HIV 阳性个体中，这些个体伴有 NCI（P<0.05），提示髓样细胞可能是 HIV 感染期间 CSF 细胞外囊泡的潜在来源。
在接受 cART 治疗的 HIV 阳性个体中，NCI 患者的 CSF 细胞外囊泡与神经元损伤生物标志物 NFL 呈正相关，这表明它们可能作为 CNS 损伤的新型生物标志物。
