Modulation of Natural Killer Cell Activity by Simian Immunodeficiency Virus Peptides

Background: Natural killer (NK) cells recognize and kill virus-infected cells without prior antigenic stimulation. This recognition is achieved in part through the loss of interactions between inhibitory killer-cell immunoglobulin-like receptors (KIRs) on NK cells and their MHC class I ligands on virus-infected cells. MHC class I-bound peptides can affect NK cell activation by stabilizing or disrupting interactions with KIRs. We previously reported that the binding of a common MHC class I molecule in the rhesus macaque, Mamu-A1*002 (A1*002), to an inhibitory KIR, Mamu-KIR3DL05 (3DL05), is stabilized by certain SIV peptides, but not by others. Methodology: Using an A1*002-expressing, transporter associated with antigen processing (TAP)-inhibited cell line pulsed with individual peptides, we evaluated 75 SIV peptides previously shown to bind to A1*002 (IC50<500 nM) for the ability to modulate the activity of primary 3DL05+ NK cells in cytotoxicity assays. Additional assays were also performed to identify peptide variants that differentially affect interactions with 3DL05 without altering binding to A1*002. Results: We identified 26 SIV peptides that suppressed the cytolytic activity of 3DL05+ NK cells, three of which correspond to immunodominant CD8+ T cell epitopes that bind to A1*002 with a high affinity (IC50<10 nM), and are therefore likely to be among the most abundant epitopes presented on the surface of SIV-infected A1*002+ cells. An analysis of peptide variants revealed that substitutions at positions 7 or 8 could change a peptide that suppresses 3DL05+ NK cell activity into a peptide that does not, and vice versa, without affecting binding to A1*002. In competition assays, the suppressive peptide dominated to inhibit 3DL05+ NK cell activity when present at less than 2% of a mixture with a non-suppressive variant of the same peptide. Conclusions: Our results demonstrate that viral peptides can modulate NK cell activation via KIR-MHC class I interactions. The dominance of suppressive peptides over non-suppressive peptides is consistent with the need to prevent NK cell activation in response to the complex repertoire of self peptides presented by MHC class I molecules on the surface of healthy cells. These observations also suggest that immunodeficiency viruses may acquire changes in epitopes that increase the avidity of MHC class I ligands for inhibitory KIRs as a mechanism of immune evasion to suppress the activation of certain NK cell subsets.