Shieh T M, Carter D L, Blosser R L, Mankowski J L, Zink M C, Clements J E
Division of Comparative Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
J Neurovirol. 2001 Feb;7(1):11-24. doi: 10.1080/135502801300069593.
Clearance of HIV and SIV from the peripheral blood by the cellular immune system lessens the viral burden in infected individuals and may have an impact on virus infection of the CNS and the development of CNS lesions. However, the role of immune responses in preventing or limiting CNS infection has not been clearly defined. We investigated the role of natural killer cells in the outcome of SIV infection of macaques as a model for humans with AIDS and HIV encephalitis. In our study, six pig-tailed macaques were infected with the neurovirulent virus, SIV/17E-Fr, and the immunosuppressive virus, SIV/ DeltaB670, in a model system that causes rapid progression to AIDS and a high frequency of CNS lesions. NK lytic activity in each macaque was monitored longitudinally. In addition, we enumerated NK cells and tested macaque PBMC for the ability to lyse SIV-infected target cells. We found that there was a significant inverse correlation (P=0.02) between the robustness of NK response and the development of CNS lesions. Animals lacking strong NK cell responses developed more severe CNS lesions than those with robust NK responses did. Furthermore, pre-infection levels of NK activity were predictive of CNS lesion severity. The macaque with the most robust pre-infection NK activity developed no CNS lesions. In these infected macaques, NK activity was shown to be directed against SIV-infected cells. We extended these in vivo findings to delineate precisely which cell type was mediating this SIV-directed lysis. We used both macaque and human cells to demonstrate that the population that mediated anti-SIV and anti-HIV cytolytic effects was NK cells. Furthermore, we showed that this anti-SIV and anti-HIV cytolytic effect was directed at the envelope protein and not gag proteins. Thus, NK cells have the capacity to recognize and lyse cells expressing SIV and HIV antigens. These data support a role for NK cells in the modulation of CNS disease.
细胞免疫系统清除外周血中的HIV和SIV可减轻感染个体的病毒载量，并可能影响中枢神经系统的病毒感染及中枢神经系统病变的发展。然而，免疫反应在预防或限制中枢神经系统感染中的作用尚未明确界定。我们以感染艾滋病和HIV脑炎的人类为模型，研究了自然杀伤细胞在猕猴感染SIV结果中的作用。在我们的研究中，6只猪尾猕猴在一个可快速发展为艾滋病且中枢神经系统病变发生率高的模型系统中，感染了神经毒性病毒SIV/17E-Fr和免疫抑制病毒SIV/DeltaB670。纵向监测每只猕猴的NK细胞杀伤活性。此外，我们对NK细胞进行计数，并检测猕猴外周血单核细胞裂解SIV感染靶细胞的能力。我们发现NK反应的强度与中枢神经系统病变的发展之间存在显著的负相关（P=0.02）。缺乏强烈NK细胞反应的动物比具有强烈NK反应的动物发生更严重的中枢神经系统病变。此外，感染前的NK活性水平可预测中枢神经系统病变的严重程度。感染前NK活性最强的猕猴未发生中枢神经系统病变。在这些感染的猕猴中，NK活性显示针对SIV感染的细胞。我们扩展了这些体内研究结果，以精确确定哪种细胞类型介导这种针对SIV的裂解作用。我们使用猕猴和人类细胞来证明介导抗SIV和抗HIV细胞溶解作用的细胞群体是NK细胞。此外，我们表明这种抗SIV和抗HIV细胞溶解作用针对的是包膜蛋白而非gag蛋白。因此，NK细胞有能力识别并裂解表达SIV和HIV抗原的细胞。这些数据支持NK细胞在调节中枢神经系统疾病中的作用。
