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Nature Genetics 39, 733–740 (1 June 2007) | doi:10.1038/ng2035

Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1

Maureen P Martin , Ying Qi , Xiaojiang Gao , Eriko Yamada , Jeffrey N Martin , Florencia Pereyra , Sara Colombo , Elizabeth E Brown , W Lesley Shupert , John Phair , James J Goedert , Susan Buchbinder , Gregory D Kirk , Amalio Telenti , Mark Connors , Stephen J O'Brien , Bruce D Walker , Peter Parham , Steven G Deeks , Daniel W McVicar & Mary Carrington

Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)+ individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes. The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection.