title: Antibody-Dependent Cellular Cytotoxicity Activity of Effector Cells from HIV-Infected Elite and Viral Controllers.
abstract: Carriage of alleles encoding certain inhibitory natural killer (NK) cell receptor/HLA ligand KIR3DL1/HLA-B combinations is associated with protection from HIV infection and slow time to AIDS, implicating NK cells in HIV control. NK cells also mediate antibody-dependent cellular cytotoxicity (ADCC). ADCC has been identified as a correlate of protection in secondary analyses of the modestly protective RV144 Thai HIV vaccine trial. In ADCC, HIV envelope (Env)-specific antibodies (Abs) bridge HIV-infected or gp120-coated target cells and NK cells expressing CD16 receptors for Ab Fc domains. CD16 engagement activates NK cells to secrete cytokines/chemokines, degranulate, deliver granzyme B (GrB) to target cells, and cytolysis. A subset of HIV+ subjects, known as slow progressors (SPs), maintains low-level viremia without treatment. HIV+ SPs versus progressors have higher titers and/or a greater breadth of ADCC-competent Abs. Investigations of the functional capacity of NK effector cells following CD16 engagement in HIV+ subjects are lacking. We used the ADCC-GranToxiLux (ADCC-GTL) assay to assess the frequency of GrB+ (%GrB+) cells generated by effector cells from 37 HIV+ SPs and 15 progressors to gp120-coated CEM.NKr.CCR5 target cells in the presence of anti-Env Abs. Subject groups were stratified according to whether or not they carried educating KIR3DL1/HLA-B combinations able to confer NK cells with functional potential. No differences were observed in %GrB+ target cells generated by effector cells from carriers of educating versus noneducating KIR3DL1/HLA-B pairs. The absence of an effect of NK cell education on this readout may be due to loss of the ability of educated NK cells from SPs to respond to Ab-dependent stimulation and/or the lower frequency of KIR3DL1+than KIR3DL1-NK cells that coexpress CD16. That KIR/HLA genotypes have minimal impact on interindividual differences in ADCC potency has relevance for therapeutic interventions that target ADCC for HIV control.
authors: 1 Research Institute of the McGill University Health Centre (RI-MUHC) , Montreal, Canada .|2 Division of Experimental Medicine, McGill University , Montreal, Canada .
authors: Gamze
authors: G
authors: Isitman
authors: 1 Research Institute of the McGill University Health Centre (RI-MUHC) , Montreal, Canada .|2 Division of Experimental Medicine, McGill University , Montreal, Canada .
authors: Irene
authors: I
authors: Lisovsky
authors: 1 Research Institute of the McGill University Health Centre (RI-MUHC) , Montreal, Canada .|2 Division of Experimental Medicine, McGill University , Montreal, Canada .
authors: Alexandra
authors: A
authors: Tremblay-McLean
authors: 3 Maple Leaf Medical Clinic, University of Toronto , Toronto, Canada .
authors: Colin
authors: C
authors: Kovacs
authors: 4 Department of Family Practice, Faculty of Medicine, University of British Columbia , Vancouver, Canada .|5 Division of AIDS, Department of Medicine, Faculty of Medicine, University of British Columbia , Vancouver, Canada .
authors: Marianne
authors: M
authors: Harris
authors: 1 Research Institute of the McGill University Health Centre (RI-MUHC) , Montreal, Canada .|6 Chronic Viral Illness Service, MUHC , Montreal, Canada .|7 Division of Hematology, MUHC , Montreal, Canada .
authors: Jean-Pierre
authors: JP
authors: Routy
authors: 8 Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM) , Montreal, Canada .|9 Department of Family Medicine, Université de Montréal , Montreal, Canada .
authors: Julie
authors: J
authors: Bruneau
authors: 10 McGill AIDS Center, Lady Davis Institute, Jewish General Hospital, McGill University , Montreal, Canada .
authors: Mark A
authors: MA
authors: Wainberg
authors: 8 Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM) , Montreal, Canada .|11 Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, Université de Montréal , Montreal, Canada .
authors: Cécile
authors: C
authors: Tremblay
authors: 1 Research Institute of the McGill University Health Centre (RI-MUHC) , Montreal, Canada .|2 Division of Experimental Medicine, McGill University , Montreal, Canada .|6 Chronic Viral Illness Service, MUHC , Montreal, Canada .|12 Division of Clinical Immunology , MUHC, Montreal, Canada .
authors: Nicole F
authors: NF
authors: Bernard
mesh_terms: D000906:Antibodies; D000920:Antibody-Dependent Cell Cytotoxicity; D015331:Cohort Studies; D005838:Genotype; D015658:HIV Infections / Q000276:immunology*; D020276:HIV Long-Term Survivors; D015235:HLA-B Antigens / Q000235:genetics; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008137:Longitudinal Studies; D054341:Receptors, KIR3DL1 / Q000235:genetics
chemical_list: D000906:Antibodies; D015235:HLA-B Antigens; C515083:KIR3DL1 protein, human; D054341:Receptors, KIR3DL1
keywords: ADCC; HIV; HLA; KIR; NK cells; slow progressors