Schafer, Jamie L.Ries, MoritzGuha, NatashaConnole, MichelleColantonio, Arnaud D.Wiertz, Emmanuel J.Wilson, Nancy A.Kaur, AmitinderEvans, David T.2015-10-012015Schafer, Jamie L., Moritz Ries, Natasha Guha, Michelle Connole, Arnaud D. Colantonio, Emmanuel J. Wiertz, Nancy A. Wilson, Amitinder Kaur, and David T. Evans. 2015. “Suppression of a Natural Killer Cell Response by Simian Immunodeficiency Virus Peptides.” PLoS Pathogens 11 (9): e1005145. doi:10.1371/journal.ppat.1005145. http://dx.doi.org/10.1371/journal.ppat.1005145.1553-7366http://nrs.harvard.edu/urn-3:HUL.InstRepos:22857013Natural killer (NK) cell responses in primates are regulated in part through interactions between two highly polymorphic molecules, the killer-cell immunoglobulin-like receptors (KIRs) on NK cells and their major histocompatibility complex (MHC) class I ligands on target cells. We previously reported that the binding of a common MHC class I molecule in the rhesus macaque, Mamu-A1*002, to the inhibitory receptor Mamu-KIR3DL05 is stabilized by certain simian immunodeficiency virus (SIV) peptides, but not by others. Here we investigated the functional implications of these interactions by testing SIV peptides bound by Mamu-A1*002 for the ability to modulate Mamu-KIR3DL05+ NK cell responses. Twenty-eight of 75 SIV peptides bound by Mamu-A1*002 suppressed the cytolytic activity of primary Mamu-KIR3DL05+ NK cells, including three immunodominant CD8+ T cell epitopes previously shown to stabilize Mamu-A1*002 tetramer binding to Mamu-KIR3DL05. Substitutions at C-terminal positions changed inhibitory peptides into disinhibitory peptides, and vice versa, without altering binding to Mamu-A1*002. The functional effects of these peptide variants on NK cell responses also corresponded to their effects on Mamu-A1*002 tetramer binding to Mamu-KIR3DL05. In assays with mixtures of inhibitory and disinhibitory peptides, low concentrations of inhibitory peptides dominated to suppress NK cell responses. Consistent with the inhibition of Mamu-KIR3DL05+ NK cells by viral epitopes presented by Mamu-A1*002, SIV replication was significantly higher in Mamu-A1*002+ CD4+ lymphocytes co-cultured with Mamu-KIR3DL05+ NK cells than with Mamu-KIR3DL05- NK cells. These results demonstrate that viral peptides can differentially affect NK cell responses by modulating MHC class I interactions with inhibitory KIRs, and provide a mechanism by which immunodeficiency viruses may evade NK cell responses.en-USJournal Article2015-10-0110.1371/journal.ppat.1005145