title: HIV infection abrogates the functional advantage of natural killer cells educated through KIR3DL1/HLA-Bw4 interactions to mediate anti-HIV antibody-dependent cellular cytotoxicity.
abstract: Combinations of KIR3DL1 and HLA-Bw4 alleles protect against HIV infection and/or disease progression. These combinations enhance NK cell responsiveness through the ontological process of education. However, educated KIR3DL1(+) NK cells do not have enhanced degranulation upon direct recognition of autologous HIV-infected cells. Since antibody-dependent cellular cytotoxicity (ADCC) is associated with improved HIV infection outcomes and NK cells overcome inhibition through killer cell immunoglobulin-like receptors (KIR) to mediate ADCC, we hypothesized that KIR3DL1-educated NK cells mediate anti-HIV ADCC against autologous cells. A whole-blood flow cytometry assay was used to evaluate ADCC-induced activation of NK cells. This assay assessed activation (gamma interferon [IFN-γ] production and/or CD107a expression) of KIR3DL1(+) and KIR3DL1(-) NK cells, from HLA-Bw4(+) and HLA-Bw4(-) HIV-positive and HIV-negative individuals, in response to autologous HIV-specific ADCC targets. KIR3DL1(+) NK cells were more functional than KIR3DL1(-) NK cells from HLA-Bw4(+), but not HLA-Bw4(-), healthy controls. In HIV-infected individuals, no differences in NK cell functionality were observed between KIR3DL1(+) and KIR3DL1(-) NK cells in HLA-Bw4(+) individuals, consistent with dysfunction of NK cells in the setting of HIV infection. Reflecting the partial normalization of NK cell responsiveness following initiation of antiretroviral therapy, a significant correlation was observed between the peripheral CD4(+) T-lymphocyte counts in antiretroviral therapy-treated subjects and the functionality of NK cells. However, peripheral CD4(+) T-lymphocyte counts were not correlated with an anti-HIV ADCC functional advantage in educated KIR3DL1(+) NK cells. The abrogation of the functional advantage of educated NK cells may enhance HIV disease progression. Strategies to enhance the potency of NK cell-mediated ADCC may improve HIV therapies and vaccines.
authors.affiliation: Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Parsons
authors.forename: Leia
authors.initials: L
authors.lastname: Wren
authors.forename: Gamze
authors.initials: G
authors.lastname: Isitman
authors.forename: Marjon
authors.initials: M
authors.lastname: Navis
authors.forename: Ivan
authors.initials: I
authors.lastname: Stratov
authors.forename: Nicole F
authors.initials: NF
authors.lastname: Bernard
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kent
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D023241:Antiretroviral Therapy, Highly Active; D016022:Case-Control Studies; D006678:HIV / Q000276:immunology*; D015483:HIV Antibodies / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D015235:HLA-B Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D011379:Prognosis; D011485:Protein Binding / Q000276:immunology; D054341:Receptors, KIR3DL1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D015483:HIV Antibodies; D015235:HLA-B Antigens; C042388:HLA-Bw4 antigen; D054341:Receptors, KIR3DL1