Ellis R J, Gamst A C, Capparelli E, Spector S A, Hsia K, Wolfson T, Abramson I, Grant I, McCutchan J A
Department of Neurosciences, HIV Neurobehavioral Research Center, University of California, San Diego, USA.
Neurology. 2000 Feb 22;54(4):927-36. doi: 10.1212/wnl.54.4.927.
To identify the sources of HIV virions in CSF by modeling treatment-associated HIV dynamics.
We postulated a model in which cell-free CSF virions originate from two major sources, namely, systemic non-CNS and CNS tissues, the latter including brain parenchyma and meninges. The model predicted that with initiation of antiretroviral therapy, the acute-phase decline in CSF HIV RNA levels would be controlled by the kinetics of the dominant virion source (systemic versus CNS). Based on prior observations, we hypothesized that the dominant source of CSF virions would shift from systemic to CNS in more advanced disease.
Three patient groups were studied: Group 1 (n = 5): nondemented, with early HIV disease (CD4+ lymphocytes > or = 400/microL) or pleocytosis (CSF leukocytes > or = 4/microL); Group 2 (n = 5): nondemented, with advanced HIV disease (CD4+ < 400/microL) and no pleocytosis; Group 3 (n = 2): patients with HIV-associated dementia (HAD). All patients began a new, highly active antiretroviral treatment regimen and underwent serial lumbar punctures and phlebotomies.
For patients in Group 2, the rate of decline in CSF HIV RNA was slower than in plasma (p < 0.00001). For Group 1, the rate of decline in CSF was not different from plasma (p > 0.25). Patients with HAD showed high CSF HIV RNA after 5 to 6 weeks of treatment despite a 100-fold decrease in plasma HIV RNA.
CSF and plasma HIV dynamics became increasingly independent in advanced HIV disease, and the compartmental discrepancy was largest in HAD. Our findings suggest that viral replication in CNS tissues may constitute a major, independent source of CSF HIV RNA. In patients with HAD, brain parenchyma itself may be the principal CNS tissue source, and CNS-targeted treatment strategies may be required to eradicate this infection.
通过模拟与治疗相关的HIV动态变化来确定脑脊液（CSF）中HIV病毒颗粒的来源。
我们提出了一个模型，其中游离的脑脊液病毒颗粒来自两个主要来源，即全身非中枢神经系统（CNS）组织和中枢神经系统组织，后者包括脑实质和脑膜。该模型预测，随着抗逆转录病毒治疗的开始，脑脊液中HIV RNA水平的急性期下降将由主要病毒颗粒来源（全身与中枢神经系统）的动力学控制。基于先前的观察结果，我们假设在疾病进展更严重时，脑脊液病毒颗粒的主要来源将从全身转移至中枢神经系统。
研究了三组患者：第1组（n = 5）：无痴呆，患有早期HIV疾病（CD4 +淋巴细胞≥400/μL）或有细胞增多症（脑脊液白细胞≥4/μL）；第2组（n = 5）：无痴呆，患有晚期HIV疾病（CD4 + < 400/μL）且无细胞增多症；第3组（n = 2）：患有HIV相关痴呆（HAD）的患者。所有患者开始新的高效抗逆转录病毒治疗方案，并接受系列腰椎穿刺和静脉穿刺。
对于第2组患者，脑脊液中HIV RNA的下降速率比血浆中慢（p < 0.00001）。对于第1组，脑脊液的下降速率与血浆无差异（p > 0.25）。尽管血浆中HIV RNA下降了100倍，但患有HAD的患者在治疗5至6周后脑脊液中HIV RNA仍很高。
在晚期HIV疾病中，脑脊液和血浆中的HIV动态变化越来越独立，且在HAD中这种区室差异最大。我们的研究结果表明，中枢神经系统组织中的病毒复制可能是脑脊液中HIV RNA的主要独立来源。在患有HAD的患者中，脑实质本身可能是主要的中枢神经系统组织来源，可能需要针对中枢神经系统的治疗策略来根除这种感染。
