Article first published online: 4 OCT 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 4, pages 1214–1222, October 2012
How to Cite
Golden-Mason, L., Stone, A. E.L., Bambha, K. M., Cheng, L. and Rosen, H. R. (2012), Race- and gender-related variation in natural killer p46 expression associated with differential anti-hepatitis c virus immunity. Hepatology, 56: 1214–1222. doi: 10.1002/hep.25771
Potential conflict of interest: Nothing to report.
The authors thank Dr. Takaji Wakita (National Institute of Infectious Diseases) for kindly providing the JFH-1 plasmid. The authors thank the Colorado Center for AIDS Research Laboratory Core for access to FACS sorting.
- Issue published online: 4 OCT 2012
- Article first published online: 4 OCT 2012
- Accepted manuscript online: 13 APR 2012 12:43PM EST
- Manuscript Accepted: 14 MAR 2012
- Manuscript Received: 5 JAN 2012
- VA Merit Review Grant. Grant Number: NIH grants U19 AI 1066328 and K24AI083742
Major racial and gender differences have been documented in the natural history and treatment responses of chronic hepatitis C virus (HCV) infection; however, distinct mechanisms have remained enigmatic. We hypothesized that racial- and gender-related differences in natural killer (NK) cell populations may explain altered natural history and treatment responses. Our study cohort consisted of 29 African-American (AA; 55% male) and 29 Caucasian-American (CA; 48% male) healthy uninfected control subjects. Multiparameter flow cytometric analysis was used to characterize levels, phenotype with respect to 14 NK receptors, and lymphokine-activated killing (LAK) function. Gene expression was assessed by real-time reverse-transcriptase polymerase chain reaction after 6-hour in vitro stimulation with Toll-like receptor (TLR) ligands. The ability to control HCV infection was assessed in the Huh-7.5/JFH-1 coculture system. NK expression of natural cytotoxicity receptor NKp46 was strongly associated with CA race and female gender and correlated positively with LAK activity (P = 0.0054). NKp46high NKs were more efficient at controlling HCV than their NKp46low counterparts (P < 0.001). Similarly, ligation of NKp46 on isolated NK cells resulted in a significant reduction in the HCV copy number detected in Huh-7.5/JFH-1 coculture (multiplicity of infection: 0.01) at an effector:target ratio of 5:1 (P < 0.005). After TLR stimulation, genes involved in cytotoxicity, but not cytokine genes, were significantly up-regulated in NKp46high NKs. Cytokine stimulation (interleukin [IL]-12 and IL-15) demonstrated that NKp46high NK cells have significantly higher interferon-gamma production than NKp46low cells. TLR stimulation significantly induced degranulation as well as tumor necrosis factor alpha (TNF-α)-related apoptosis-inducing ligand, Fas, and TNF-α protein expression in NKp46high NKs. NKp46 ligand was induced on HCV-infected hepatocytes. Conclusions: NKp46 expression may contribute to differential HCV responses. NKp46 expression correlates with anti-HCV activity in vitro and thus may prove to be a useful therapeutic target. (HEPATOLOGY 2012)