Natural killer inhibitory receptor expression associated... : Hepatology (original) (raw)

Viral Hepatitis

Natural killer inhibitory receptor expression associated with treatment failure and interleukin-28B genotype in patients with chronic hepatitis C

Golden-Mason, Lucy1,2; Bambha, Kiran M.1; Cheng, Linling1; Howell, Charles D.3; Taylor, Milton W.4; Clark, Paul J.5; Afdhal, Nezam6; Rosen, Hugo R.1,2,7,* on behalf of the Virahep-C Study Group

1_Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver & National Jewish Hospital, Denver CO_

2_Integrated Program in Immunology, University of Colorado Denver & National Jewish Hospital, Denver CO_

3_University of Maryland Baltimore School of Medicine, Baltimore, MD_

4_Department of Biology, Indiana University, Bloomington, IN_

5_Duke Clinical Research Institute and Division of Gastroenterology, Duke University Medical Center, School of Medicine, Duke University, Durham, NC_

6_Beth Israel Deaconess Medical Center, Boston, MA_

7_Denver VA Medical Center, Denver, CO_

*Address reprint requests to: Division of GI/Hepatology B-158, Academic Office Building 1, 12631 E. 17th Ave., Rm. 7614, PO Box 6511, Aurora, CO 80045

Additional Supporting Information may be found in the online version of this article.

Email: [email protected]

Published online 24 August 2011 in Wiley Online Library(wileyonlinelibrary.com).

Potential conflict of interest: Dr. Howell advises Roche. He advises and received grants from Vertex. He also received grants from Eisai.

Supported by RO1 DK071560 (to H.R.R.) and by NIDDK 1 K24 DK072036-01. (to. C.D.H). This study was funded as a cooperative agreement by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Intramural Research Program of the National Cancer Institute (NCI) with further support under a Cooperative Research and Development Agreement (CRADA) with Roche Laboratories, Inc. A complete listing of participants in the Virahep-C study is given in Reference 5. Grant numbers: U01 DK60329, U01 DK60340, U01 DK60324, U01 DK60344, U01 DK60327, U01 DK60335, U01 DK60352, U01 DK60342, U01 DK60345, U01 DK60309, U01 DK60346, U01 DK60349, U01 DK60341. Dr. Howell is supported by NIDDK 1 K24 DK072036-01. Dr. Clark received funding support from the National Health and Medical Research Council of Australia, the Duke Clinical Research Institute, the Richard Boebel Family Fund, the National Centre in HIV Epidemiology and Clinical Research (now the Kirby Institute for Infection and Immunity in Society), University of New South Wales, Australia.

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Abstract

Natural killer (NK) cells constitute a first line of defense against viral infections; their function is governed by the integration of signals from multiple activating and inhibitory surface receptors. We hypothesized that because NKs become rapidly activated by cytokines, response to anti-hepatitis C virus (HCV) therapy would be predicted by the phenotype and function of NKs. We used a cohort of 101 patients (55 African, 46 Caucasian-American) who received pegylated-interferon (IFN) and ribavirin for 48 weeks. Multiparameter FACS analysis was used to examine relative expression of 14 different inhibitory/activating receptors. Interleukin (IL)-28B genotyping (rs12979860) was also performed. Pretreatment levels of inhibitory receptors CD158a, CD158b, and CD158e were higher in patients who demonstrated poor viral decline within the first 28 days of therapy. Higher expression levels of inhibitory receptors NKG2A, CD158b, and CD158e were demonstrable in patients who failed to achieve sustained virologic response (SVR). Patients carrying the IL-28B T allele had higher NKG2A expression on effector NKs. We created a mathematical regression model incorporating race, viral level, and two inhibitory receptors. The area-under-the curve was 0.88, which is highly predictive of SVR. Moreover, the model performed complementarily with IL-28B across the CC, CT, and TT genotypes. Purified NKG2Aneg NKs treated with pegylated-IFN-α for 4 hours demonstrated higher levels of IFN-γ-inducible protein-10 (IP-10) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) compared with their NKG2Apos counterparts. Conclusions: These results provide novel insights into the associations of NK phenotype with IL-28B genotype and gene expression patterns, as well as the role of NKs in mediating IFN-induced viral clearance of chronic HCV infection. (Hepatology 2011;)