Increased frequency and function of KIR2DL1-3 super(+) NK cells in primary HIV-1 infection are determined by HLA-C group haplotypes

• Published in: European journal of immunology 2014-10, Vol.44 (10), p.2938-2948
• Main Authors: Korner, Christian, Granoff, Mitchell E, Amero, Molly A, Sirignano, Michael N, Vaidya, Sagar A, Jost, Stephanie, Allen, Todd M, Rosenberg, Eric S, Altfeld, Marcus
• Format: Article
• Language: English
• Subjects: Human immunodeficiency virus 1
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201444751

The acquisition and maintenance of NK-cell function is mediated by inhibitory killer-cell immunoglobulin-like receptors (KIRs) through their interaction with HLA class I molecules. Recently, HLA-C expression levels were shown to be correlated with protection against multiple outcomes of HIV-1 infection; however, the underlying mechanisms are poorly understood. As HLA-C is the natural ligand for the inhibitory receptors KIR2DL1 and KIR2DL2/3, we sought to determine whether HLA-C group haplotypes affect NK-cell responses during primary HIV-1 infection. The phenotypes and functional capacity of NK cells derived from HIV-1-positive and HIV-1-negative individuals were assessed (N = 42 and N = 40, respectively). HIV-1 infection was associated with an increased frequency of KIR2DL1-3 super(+) NK cells. Further analysis showed that KIR2DL1 super(+) NK cells were selectively increased in individuals homozygous for HLA-C2, while HLA-C1-homozygous individuals displayed increased proportions of KIR2DL2/3 super(+) NK cells. KIR2DL1-3 super(+) NK cells were furthermore more polyfunctional during primary HIV-1 infection in individuals also encoding for their cognate HLA-C group haplotypes, as measured by degranulation and IFN- gamma and TNF- alpha production. These results identify a novel relationship between HLA-C and KIR2DL super(+) NK-cell subsets and demonstrate that HLA-C-mediated licensing modulates NK-cell responses to primary HIV-1 infection.