The Influence of Hepatitis C Viral Loads on Natural Killer Cell Function

Mark Collister, Cindy Ellison, Qian Li, Gerald Y. Minuk, Julia D. Rempel, Sam K. Kung

Abstract


Background: 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.

Methods: 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.

Results: 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 in vitro (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.

Conclusions: High HCV loads appear to promote NK exhaustion in chronic HCV infection.




Gastroenterol Res. 2019;12(1):8-15
doi: https://doi.org/10.14740/gr1081w


Keywords


NK cells; Hepatitis C; Cytotoxicity; IFN-gamma; PD-1

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