HIV exposed seronegative (HESN) compared to HIV infected individuals have higher frequencies of telomeric Killer Immunoglobulin-like Receptor (KIR) B motifs; Contribution of KIR B motif encoded genes to NK cell responsiveness

PLoS One. 2017 Sep 22;12(9):e0185160. doi: 10.1371/journal.pone.0185160. eCollection 2017.

Abstract

Previously, we showed that Killer Immunoglobulin-like Receptor (KIR)3DS1 homozygotes (hmz) are more frequent in HIV exposed seronegative (HESN) than in recently HIV infected (HIV+) individuals. KIR3DS1 encodes an activating Natural Killer (NK) cell receptor (NKR). The link between KIR genotype and HIV outcomes likely arises from the function that NK cells acquire through expression of particular NKRs. An initial screen of 97 HESN and 123 HIV+ subjects for the frequency of KIR region gene carriage observed between-group differences for several telomeric KIR region loci. In a larger set of up to 106 HESN and 439 HIV+ individuals, more HESN than HIV+ subjects were KIR3DS1 homozygotes, lacked a full length KIR2DS4 gene and carried the telomeric group B KIR haplotype motif, TB01. TB01 is characterized by the presence of KIR3DS1, KIR2DL5A, KIR2DS3/5 and KIR2DS1, in linkage disequilibrium with each other. We assessed which of the TB01 encoded KIR gene products contributed to NK cell responsiveness by stimulating NK cells from 8 HIV seronegative KIR3DS1 and TB01 motif homozygotes with 721.221 HLA null cells and evaluating the frequency of KIR3DS1+/-KIR2DL5+/-, KIR3DS1+/-KIR2DS1+/-, KIR3DS1+/-KIR2DS5+/- NK cells secreting IFN-γ and/or expressing CD107a. A higher frequency of NK cells expressing, versus not, KIR3DS1 responded to 721.221 stimulation. KIR2DL5A+, KIR2DS1+ and KIR2DS5+ NK cells did not contribute to 721.221 responses or modulate those by KIR3DS1+ NK cells. Thus, of the TB01 KIR gene products, only KIR3DS1 conferred responsiveness to HLA-null stimulation, demonstrating its ligation can activate ex vivo NK cells.

MeSH terms

  • Cells, Cultured
  • Coculture Techniques
  • Gene Frequency
  • Genetic Load
  • HIV Infections / genetics
  • HIV Infections / immunology*
  • HIV Seronegativity*
  • HLA Antigens / immunology
  • Haplotypes
  • Humans
  • Killer Cells, Natural / immunology*
  • Linkage Disequilibrium
  • Lymphocyte Activation*
  • Prospective Studies
  • Receptors, KIR / genetics
  • Receptors, KIR / metabolism
  • Receptors, KIR2DL5 / genetics
  • Receptors, KIR2DL5 / metabolism
  • Receptors, KIR3DS1 / chemistry
  • Receptors, KIR3DS1 / genetics*
  • Receptors, KIR3DS1 / metabolism*
  • Telomere

Substances

  • HLA Antigens
  • KIR2DS1 protein, human
  • KIR2DS5 protein, human
  • Receptors, KIR
  • Receptors, KIR2DL5
  • Receptors, KIR3DS1

Grants and funding

This work was supported by Canadian Institutes for Health Research grants MOP-142494 and MOP-103230 to NFB; Canadian HIV Trials Network grant CTN-257 to J-PR; Fonds de Recherche du Québec–Santé, AIDS and Infectious Diseases Network infrastructure grant to Dr. Nicole F. Bernard; Fonds de Recherche du Québec-Santé AIDS and Infectious Diseases Network PhD. scholarship grant to IL; Canadian Institutes for Health Research Ph.D. scholarship to IL; Partial support from the Fonds de Recherche du Québec-Santé to the Research Institute of the McGill University Health Center of which NFB and J-PR are members.