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Science 6 August 2004:
Vol. 305. no. 5685, pp. 872 - 874
DOI: 10.1126/science.1097670
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Reports

HLA and NK Cell Inhibitory Receptor Genes in Resolving Hepatitis C Virus Infection

Salim I. Khakoo,1* Chloe L. Thio,2 Maureen P. Martin,3 Collin R. Brooks,1 Xiaojiang Gao,3 Jacquie Astemborski,2 Jie Cheng,3 James J. Goedert,4 David Vlahov,5 Margaret Hilgartner,6 Steven Cox,7 Ann-Margeret Little,7 Graeme J. Alexander,8 Matthew E. Cramp,9 Stephen J. O'Brien,10 William M. C. Rosenberg,1 David L. Thomas,2 Mary Carrington3*

Natural killer (NK) cells provide a central defense against viral infection by using inhibitory and activation receptors for major histocompatibility complex class I molecules as a means of controlling their activity. We show that genes encoding the inhibitory NK cell receptor KIR2DL3 and its human leukocyte antigen C group1 (HLA-C1) ligand directly influence resolution of hepatitis C virus (HCV) infection. This effect was observed in Caucasians and African Americans with expected low infectious doses of HCV but not in those with high-dose exposure, in whom the innate immune response is likely overwhelmed. The data strongly suggest that inhibitory NK cell interactions are important in determining antiviral immunity and that diminished inhibitory responses 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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Y.-M. A. Chen, S.-Y. Liang, Y.-P. Shih, C.-Y. Chen, Y.-M. Lee, L. Chang, S.-Y. Jung, M.-S. Ho, K.-Y. Liang, H.-Y. Chen, et al. (2006)
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J. Immunol. 176, 1141-1147
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Requisite H2k Role in NK Cell-Mediated Resistance in Acute Murine Cytomegalovirus-Infected MA/My Mice.
A. Dighe, M. Rodriguez, P. Sabastian, X. Xie, M. McVoy, and M. G. Brown (2005)
J. Immunol. 175, 6820-6828
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J. Immunol. 175, 5006-5015
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Shared Alterations in NK Cell Frequency, Phenotype, and Function in Chronic Human Immunodeficiency Virus and Hepatitis C Virus Infections.
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J. Virol. 79, 12365-12374
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Blood 106, 2252-2258
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F. Gays, K. Martin, R. Kenefeck, J. G. Aust, and C. G. Brooks (2005)
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Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes.
K. C. Hsu, C. A. Keever-Taylor, A. Wilton, C. Pinto, G. Heller, K. Arkun, R. J. O'Reilly, M. M. Horowitz, and B. Dupont (2005)
Blood 105, 4878-4884
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H. Yamada, S. Shimada, M. Morikawa, K. Iwabuchi, R. Kishi, K. Onoe, and H. Minakami (2005)
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Comparison of Killer Ig-Like Receptor Genotyping and Phenotyping for Selection of Allogeneic Blood Stem Cell Donors.
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J. Immunol. 174, 6540-6545
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Natural selection drives recurrent formation of activating killer cell immunoglobulin-like receptor and Ly49 from inhibitory homologues.
L. Abi-Rached and P. Parham (2005)
J. Exp. Med. 201, 1319-1332
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Understanding how combinations of HLA and KIR genes influence disease.
S. Rajagopalan and E. O. Long (2005)
J. Exp. Med. 201, 1025-1029
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Hierarchy of resistance to cervical neoplasia mediated by combinations of killer immunoglobulin-like receptor and human leukocyte antigen loci.
M. Carrington, S. Wang, M. P. Martin, X. Gao, M. Schiffman, J. Cheng, R. Herrero, A. C. Rodriguez, R. Kurman, R. Mortel, et al. (2005)
J. Exp. Med. 201, 1069-1075
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S. Johansson, M. Johansson, E. Rosmaraki, G. Vahlne, R. Mehr, M. Salmon-Divon, F. Lemonnier, K. Karre, and P. Hoglund (2005)
J. Exp. Med. 201, 1145-1155
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In Vitro and In Vivo Characterization of a Novel Antibody-Like Single-Chain TCR Human IgG1 Fusion Protein.
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J. Immunol. 174, 4381-4388
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Two Structurally Related Rat Ly49 Receptors with Opposing Functions (Ly49 Stimulatory Receptor 5 and Ly49 Inhibitory Receptor 5) Recognize Nonclassical MHC Class Ib-Encoded Target Ligands.
C. Naper, K.-Z. Dai, L. Kveberg, B. Rolstad, E. C. Niemi, J. T. Vaage, and J. C. Ryan (2005)
J. Immunol. 174, 2702-2711
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Combinations of Maternal KIR and Fetal HLA-C Genes Influence the Risk of Preeclampsia and Reproductive Success.
S. E. Hiby, J. J. Walker, K. M. O'Shaughnessy, C. W.G. Redman, M. Carrington, J. Trowsdale, and A. Moffett (2004)
J. Exp. Med. 200, 957-965
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Unlocking the Determinants of HCV Immunity.
(2004)
Journal Watch Infectious Diseases 2004, 8
   Full Text »


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