A Conserved HIV-1-Derived Peptide Presented by HLA-E Renders Infected T-cells Highly Susceptible to Attack by NKG2A/CD94-Bearing Natural Killer Cells

Major histocompatibility class i (mhc-i)-specific inhibitory receptors on natural killer (nk) cells (inkrs) tolerize mature nk cell responses toward normal cells. nk cells generate cytolytic responses to virus-infected or malignant target cells with altered or decreased mhc-i surface expression due to the loss of tolerizing ligands. the nkg2a/cd94 inkr suppresses nk cell responses through recognition of the non-classical mhc-i,hla-e. we used hiv-infected primary t-cells as targets in an in vitro cytolytic assay with autologous nk cells from healthy donors. in these experiments,primary nkg2a/cd94+ nk cells surprisingly generated the most efficient responses toward hiv-infected t-cells,despite high hla-e expression on the infected targets. since certain mhc-i-presented peptides can alter recognition by inkrs,we hypothesized that hiv-1-derived peptides presented by hla-e on infected cells may block engagement with nkg2a/cd94,thereby engendering susceptibility to nkg2a/cd94+ nk cells. we demonstrate that hla-e is capable of presenting a highly conserved peptide from hiv-1 capsid (aisprtlna) that is not recognized by nkg2a/cd94. we further confirmed that hla-c expressed on hiv-infected cells restricts attack by kir2dl+ cd56dim nk cells,in contrast to the efficient responses by cd56bright nk cells,which express predominantly nkg2a/cd94 and lack kir2dls. these findings are important since the use of nk cells was recently proposed to treat latently hiv-1-infected patients in combination with latency reversing agents. our results provide a mechanistic basis to guide these future clinical studies,suggesting that ex vivo-expanded nkg2a/cd94+ kir2dl- nk cells may be uniquely beneficial. © 2016 davis et al.