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HLA and NK Cell Inhibitory Receptor Genes in Resolving Hepatitis C Virus Infection
Salim I. Khakoo,1*Chloe L. Thio,2Maureen P. Martin,3Collin R. Brooks,1Xiaojiang Gao,3Jacquie Astemborski,2Jie Cheng,3James J. Goedert,4David Vlahov,5Margaret Hilgartner,6Steven Cox,7Ann-Margeret Little,7Graeme J. Alexander,8Matthew E. Cramp,9Stephen J. O'Brien,10William M. C. Rosenberg,1David L. Thomas,2Mary Carrington3*
Natural killer (NK) cells provide a central defense againstviral infection by using inhibitory and activation receptorsfor major histocompatibility complex class I molecules as ameans of controlling their activity. We show that genes encodingthe inhibitory NK cell receptor KIR2DL3 and its human leukocyteantigen C group1 (HLA-C1) ligand directly influence resolutionof hepatitis C virus (HCV) infection. This effect was observedin Caucasians and African Americans with expected low infectiousdoses of HCV but not in those with high-dose exposure, in whomthe innate immune response is likely overwhelmed. The data stronglysuggest that inhibitory NK cell interactions are important indetermining antiviral immunity and that diminished inhibitoryresponses confer protection against HCV.
1 Liver Group, Division of Infection, Inflammation, and Repair, Southampton University, Southampton 5016 6YD, UK. 2 Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA. 3 Basic Research Program, Scientific Applications International Corporation Frederick, Inc., Laboratory of Genomic Diversity, NCI Frederick, Frederick, MD 21702, USA. 4 Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20852, USA. 5 New York Academy of Medicine, New York, NY 10029, USA. 6 Department of Pediatrics, New York Presbyterian Hospital–Cornell Medical Center, New York, NY 10021, USA. 7 Anthony Nolan Research Institute, The Royal Free Hospital, London NW3 2PF, UK. 8 Department of Medicine, University of Cambridge, Cambridge CD2 2QQ, UK. 9 Department of Gastroenterology, Derriford Hospital, Plymouth PL6 8DH, UK. 10 Laboratory of Genomic Diversity, National Cancer Institute, Frederick, MD 21702, USA.
* To whom correspondence should be addressed: E-mail: carringt{at}ncifcrf.gov (M.C.); sik{at}soton.ac.uk (S.I.K.)
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