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

• DOI: 10.1371/journal.ppat.1005421
• Publication Date: 2016-02-01T18:54:18Z
• Authors: Zachary B. Davis; Andrew Cogswell; Hamish Scott; Amanda Mertsching; Julie Boucau; Daniel Wambua; Sylvie Le Gall; Vicente Planelles; Kerry S. Campbell; Edward Barker
• Keywords: 0301 basic medicine; QH301-705.5; T-Lymphocytes; Histocompatibility Antigens Class I; HIV Infections; HLA-C Antigens; RC581-607; 3. Good health; Killer Cells, Natural; 03 medical and health sciences; HIV-1; Humans; Receptors, Natural Killer Cell; Immunologic diseases. Allergy; Biology (General); Peptides; NK Cell Lectin-Like Receptor Subfamily D; HLA-E Antigens; Research Article

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(+) CD56(dim) NK cells, in contrast to the efficient responses by CD56(bright) 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.