Department of Microbial Molecular Biology, Novartis Vaccines and Diagnostics, Siena, Italy.
J Hepatol. 2010 Feb;52(2):183-90. doi: 10.1016/j.jhep.2009.11.003. Epub 2009 Dec 16.
BACKGROUND & AIMS: Hepatitis C virus (HCV) is remarkably successful in establishing persistent infections due to its ability to evade host immune responses through a combination of mechanisms including modulation of interferon (IFN) signalling in infected cells, interference with effector cell function of the immune system and continual viral genetic variation. We have previously demonstrated that natural killer (NK) cells can be inhibited in vitro by recombinant HCV glycoprotein E2 via cross-linking of CD81, a cellular co-receptor for the virus.
Taking advantage of the recently established tissue-culture system for HCV, we have studied the effects of CD81 engagement by the HCV envelope glycoprotein E2 when the protein is part of complete, infectious viral particles. Specifically, we asked whether exposure to HCV viral particles (HCVcc) affects activation of NK cells and whether altered NK cell activation, in turn, impacts on HCV infectivity.
We found that immobilized HCVcc, unlike soluble HCVcc, inhibited IFN-gamma production by interleukin (IL)-12 activated NK cells, and that this effect was mediated by engagement of cellular CD81 by HCV-virion displayed E2. In contrast, NK-production of IL-8 was increased in the presence of HCV. The cytokines produced by IL-12 activated NK cells strongly reduced the establishment of productive HCV infection. Importantly, NK-cell derived cytokines secreted in the presence of HCVcc showed a diminished antiviral effect that correlated with IFN-gamma reduction, while IL-8 concentrations had no impact on HCV infectivity.
Exposure to HCVcc modulates the pattern of cytokines produced by NK cells, leading to reduced antiviral activity.
由于丙型肝炎病毒 (HCV) 通过多种机制逃避宿主免疫反应，包括感染细胞中干扰素 (IFN) 信号的调节、干扰免疫系统效应细胞的功能和持续的病毒遗传变异，因此 HCV 能够非常成功地建立持续性感染。我们之前已经证明，自然杀伤 (NK) 细胞可以通过 HCV 糖蛋白 E2 与病毒的细胞共受体 CD81 的交联在体外被抑制。
利用最近建立的 HCV 组织培养系统，我们研究了当 HCV 包膜糖蛋白 E2 作为完整、感染性病毒颗粒的一部分时，CD81 与 HCV 包膜糖蛋白 E2 的结合对 NK 细胞的激活的影响，以及 NK 细胞激活的改变是否反过来影响 HCV 的感染性。
我们发现，与可溶性 HCVcc 不同，固定化 HCVcc 抑制了 IL-12 激活的 NK 细胞产生 IFN-γ，并且这种作用是由 HCV 病毒展示的 E2 与细胞 CD81 的结合介导的。相比之下，在 HCV 的存在下，NK 细胞产生的 IL-8 增加。由 IL-12 激活的 NK 细胞产生的细胞因子强烈降低了有效的 HCV 感染的建立。重要的是，在存在 HCVcc 的情况下，NK 细胞分泌的细胞因子表现出抗病毒活性降低，这与 IFN-γ减少相关，而 IL-8 浓度对 HCV 感染性没有影响。
暴露于 HCVcc 会调节 NK 细胞产生的细胞因子模式，导致抗病毒活性降低。
