Collister Mark, Ellison Cindy, Li Qian, Minuk Gerald Y, Rempel Julia D, Kung Sam K
Department of Immunology, University of Manitoba, Winnipeg, MB, Canada.
Section of Hepatology, University of Manitoba, Winnipeg, MB, Canada.
Gastroenterology Res. 2019 Feb;12(1):8-15. doi: 10.14740/gr1081w. Epub 2019 Feb 26.
Hepatitis C virus (HCV) infection has a high rate of chronicity, attributable to its capacity to alter host immunity, including natural killer (NK) cell function. In this study, the interaction between NK cell activity and HCV viral load was investigated.
Peripheral blood NK cells were examined for cytotoxicity and interferon (IFN)-γ expression in HCV infected low (LVL, < 800,000 IU/mL, n = 10) and high (HVL, > 800,000 IU/mL, n = 13) viral load patient cohorts.
Spontaneous NK cell cytotoxicity was more robust in the LVL cohort resulting in a negative correlation with viral loads (spontaneous, r = -0.437, P = 0.037; IFN-α activated, r = -0.372, P = 0.081). Although the percent of IFN-γ+ NK cells did not associate with viral load, within the LVL cohort there was a marked increase in IFN-γ+ NK cells upon IFN-α activation relative to medium alone (P < 0.01). To examine the inability of NK cells derived from HVL patients to be further activated, the expression of the exhaustion marker programmed cell death protein (PD)-1 was evaluated. PD-1 expression upon NK cell activation correlated with viral load (r = 0.649, P = 0.009). In addition, HCV proteins upregulated PD-1 expression (P < 0.05), suggesting that HCV can directly promote NK cell exhaustion. Cells from HVL patients were also more likely to produce IFN-γ in response to HCV core protein. The finding that NK cell PD-1 and IFN-γ expression are linked (r = 0.542, P < 0.05) suggests that increased IFN-γ levels may induce PD-1 as a negative feedback mechanism.
High HCV loads appear to promote NK exhaustion in chronic HCV infection.
丙型肝炎病毒（HCV）感染的慢性化率很高，这归因于其改变宿主免疫的能力，包括自然杀伤（NK）细胞功能。在本研究中，对NK细胞活性与HCV病毒载量之间的相互作用进行了研究。
在HCV感染的低病毒载量（LVL，<800,000 IU/mL，n = 10）和高病毒载量（HVL，>800,000 IU/mL，n = 13）患者队列中，检测外周血NK细胞的细胞毒性和干扰素（IFN）-γ表达。
LVL队列中的自发NK细胞细胞毒性更强，导致其与病毒载量呈负相关（自发，r = -0.437，P = 0.037；IFN-α激活，r = -0.372，P = 0.081）。虽然IFN-γ+NK细胞的百分比与病毒载量无关，但在LVL队列中，相对于单独的培养基，IFN-α激活后IFN-γ+NK细胞有显著增加（P < 0.01）。为了研究HVL患者来源的NK细胞无法被进一步激活的情况，评估了耗竭标志物程序性细胞死亡蛋白（PD）-1的表达。NK细胞激活后PD-1的表达与病毒载量相关（r = 0.649，P = 0.009）。此外，HCV蛋白上调了PD-1的表达（P < 0.05），表明HCV可直接促进NK细胞耗竭。HVL患者的细胞对HCV核心蛋白产生IFN-γ的可能性也更高。NK细胞PD-1和IFN-γ表达相关的发现（r = 0.542，P < 0.05）表明，IFN-γ水平升高可能诱导PD-1作为一种负反馈机制。
高HCV载量似乎会促进慢性HCV感染中的NK细胞耗竭。
