title: Receptor-ligand requirements for increased NK cell polyfunctional potential in slow progressors infected with HIV-1 coexpressing KIR3DL1*h/*y and HLA-B*57.
abstract: Carriage of the natural killer (NK) receptor genotype KIR3DL1*h/*y with its HLA-B*57 ligand (*h/*y+B*57) is associated with slow time to AIDS and low viral load (VL). To provide a functional basis for these epidemiological observations, we assessed whether HIV-1-infected slow progressors (SP) carrying the *h/*y+B*57 compound genotype would have increased NK cell polyfunctional potential in comparison to SP with other killer immunoglobulin-like receptor (KIR)/HLA compound genotypes and whether this enhanced polyfunctionality was dependent upon the coexpression of both KIR3DL1*h/*y and HLA-B*57. The functional potential of NK cells was investigated by stimulating peripheral blood mononuclear cells with HLA-devoid targets or single HLA transfectants. Multiparametric flow cytometry was used to detect NK cells with seven functional profiles representing all permutations of CD107a expression and gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) secretion. NK cells from individuals carrying KIR3DL1 receptor-HLA-Bw4 ligand pairs had greater trifunctional responses than those from KIR3DL1 homozygotes (hmz), who were Bw6 homozygotes. NK cells from subjects carrying the *h/*y+B*57 genotypes exhibited the highest trifunctional potential, and this was dependent on cocarriage of the NK receptor and its ligand. Trifunctional cells secreted more of each function tested on a per-cell basis than each corresponding monofunctional NK subset. Although VL influenced NK functionality, individuals with defined KIR/HLA genotypes exhibited differences in NK cell polyfunctionality that could not be accounted for by VL alone. The protective effect of HLA-B*57 on slow progression to AIDS and low VL may be mediated through its interaction with KIR3DL1 alleles to educate NK cells for potent activity upon stimulation.
authors.affiliation: Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.
authors.forename: Philomena
authors.initials: P
authors.lastname: Kamya
authors.forename: Salix
authors.initials: S
authors.lastname: Boulet
authors.forename: Christos M
authors.initials: CM
authors.lastname: Tsoukas
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Routy
authors.forename: Réjean
authors.initials: R
authors.lastname: Thomas
authors.forename: Pierre
authors.initials: P
authors.lastname: Côté
authors.forename: Mohamed-Rachid
authors.initials: MR
authors.lastname: Boulassel
authors.forename: Jean-Guy
authors.initials: JG
authors.lastname: Baril
authors.forename: Colin
authors.initials: C
authors.lastname: Kovacs
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Migueles
authors.forename: Mark
authors.initials: M
authors.lastname: Connors
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Suscovich
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Cecile L
authors.initials: CL
authors.lastname: Tremblay
authors.forename: Nicole
authors.initials: N
authors.lastname: Bernard
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000276:immunology*; D015235:HLA-B Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D008297:Male; D008875:Middle Aged; D054341:Receptors, KIR3DL1 / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D015235:HLA-B Antigens; C103707:HLA-B57 antigen; C515083:KIR3DL1 protein, human; D008024:Ligands; D054341:Receptors, KIR3DL1