Receptor-ligand requirements for increased NK cell polyfunctional potential in slow progressors infected with HIV-1 coexpressing KIR3DL1*h/*y and HLA-B*57

Philomena Kamya, Salix Boulet, Christos M. Tsoukas, Jean Pierre Routy, Réjean Thomas, Pierre Côté, Mohamed Rachid Boulassel, Jean Guy Baril, Colin Kovacs, Stephen A. Migueles, Mark Connors, Todd J. Suscovich, Christian Brander, Cecile L. Tremblay, Nicole Bernard

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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-HLABw4 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.

Original languageEnglish
Pages (from-to)5949-5960
Number of pages12
JournalJournal of Virology
Volume85
Issue number12
DOIs
Publication statusPublished - Jun 2011

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natural killer cells
Human immunodeficiency virus 1
Natural Killer Cells
HIV-1
Ligands
receptors
viral load
Viral Load
KIR3DL1 Receptors
Genotype
genotype
KIR Receptors
Homozygote
homozygosity
immunoglobulins
Acquired Immunodeficiency Syndrome
mononuclear leukocytes
HLA-B57 antigen
ligands
interferon-gamma

ASJC Scopus subject areas

  • Immunology
  • Virology

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Receptor-ligand requirements for increased NK cell polyfunctional potential in slow progressors infected with HIV-1 coexpressing KIR3DL1*h/*y and HLA-B*57. / Kamya, Philomena; Boulet, Salix; Tsoukas, Christos M.; Routy, Jean Pierre; Thomas, Réjean; Côté, Pierre; Boulassel, Mohamed Rachid; Baril, Jean Guy; Kovacs, Colin; Migueles, Stephen A.; Connors, Mark; Suscovich, Todd J.; Brander, Christian; Tremblay, Cecile L.; Bernard, Nicole.

In: Journal of Virology, Vol. 85, No. 12, 06.2011, p. 5949-5960.

Research output: Contribution to journalArticle

Kamya, P, Boulet, S, Tsoukas, CM, Routy, JP, Thomas, R, Côté, P, Boulassel, MR, Baril, JG, Kovacs, C, Migueles, SA, Connors, M, Suscovich, TJ, Brander, C, Tremblay, CL & Bernard, N 2011, 'Receptor-ligand requirements for increased NK cell polyfunctional potential in slow progressors infected with HIV-1 coexpressing KIR3DL1*h/*y and HLA-B*57', Journal of Virology, vol. 85, no. 12, pp. 5949-5960. https://doi.org/10.1128/JVI.02652-10
Kamya, Philomena ; Boulet, Salix ; Tsoukas, Christos M. ; Routy, Jean Pierre ; Thomas, Réjean ; Côté, Pierre ; Boulassel, Mohamed Rachid ; Baril, Jean Guy ; Kovacs, Colin ; Migueles, Stephen A. ; Connors, Mark ; Suscovich, Todd J. ; Brander, Christian ; Tremblay, Cecile L. ; Bernard, Nicole. / Receptor-ligand requirements for increased NK cell polyfunctional potential in slow progressors infected with HIV-1 coexpressing KIR3DL1*h/*y and HLA-B*57. In: Journal of Virology. 2011 ; Vol. 85, No. 12. pp. 5949-5960.
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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-HLABw4 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.",
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AU - Migueles, Stephen A.

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