Suppression of a Natural Killer Cell Response by Simian Immunodeficiency Virus Peptides

Natural 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. © 2015 schafer et al.