HIV protective KIR3DL1/S1-HLA-B genotypes influence NK cell-mediated inhibition of HIV replication in autologous CD4 targets.
Carriage of the genetic combination encoding a high expression inhibitory Killer Immunoglobulin-like Receptor (KIR)3DL1 with its ligand, HLA-B*57 (*h/*y+B*57) is associated with slower time to AIDS and better HIV viral load control than being a Bw6 homozygote (Bw6hmz). Natural Killer (NK) cells from *h/*y+B*57 carriers receive potent educational signals through HLA-B*57 KIR3DL1 ligation leading to high functional potential. NK cells from Bw6hmz are not educated through KIR3DL1 because Bw6 antigens do not interact with this inhibitory receptor. To better understand the impact of KIR/HLA combinations on NK cell mediated anti-viral activity we measured NK cell mediated inhibition of HIV replication in autologous infected CD4 (iCD4) cells by assessing the frequency of p24 positive CD4 targets and supernatant levels of HIV p24 longitudinally in the presence versus absence of NK cells. Forty-seven HIV uninfected subjects were studied, including carriers of *h/*y+B*57, a low expression KIR3DL1 genotype with HLA-B*57 termed *l/*x+B*57, a genotype designated 3DS1+*80I and Bw6hmz. NK cells from *h/*y+B*57 carriers, like those from 3DS1+*80I subjects, inhibited HIV replication in autologous iCD4 cells better than those from Bw6hmz and *l/*x+B*57 carriers. Cell contact between NK and iCD4 cells activated NK cells to inhibit viral replication in a non-contact dependent fashion through secretion of CC-chemokines. iCD4 stimulated NK cells from *h/*y+B*57 and 3DS1+*80I carriers produced higher levels of CC-chemokines than those from Bw6hmz or *l/*x+B*57 carriers. Higher levels of CC-chemokines were produced by KIR3DL1(+) than KIR3DL1(-) NK cells. We conclude that NK-mediated inhibition of viral replication in autologous iCD4 cells is partially due to a block at the level of HIV entry into new targets by secreted CC-chemokines.
Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada ; Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
Rujun
R
Song
Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada ; Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
Irene
I
Lisovsky
Chronic Viral Illness Service, McGill University Health Centre, Montreal, Quebec, Canada ; Department of Family Medicine, McGill University, Montreal, Quebec, Canada.
Bertrand
B
Lebouché
Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada ; Chronic Viral Illness Service, McGill University Health Centre, Montreal, Quebec, Canada ; Division of Hematology, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
Jean-Pierre
JP
Routy
Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada ; Department of Family Medicine, Université de Montréal, Montreal, Quebec, Canada.
Julie
J
Bruneau
Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada ; Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada ; Chronic Viral Illness Service, McGill University Health Centre, Montreal, Quebec, Canada ; Division of Clinical Immunology, McGill University Health Centre, Montreal, Quebec, Canada.
Nicole F
NF
Bernard
D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology*; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015497:HIV-1 / Q000502:physiology*; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D054341:Receptors, KIR3DL1 / Q000235:genetics / Q000276:immunology*; D014779:Virus Replication / Q000235:genetics / Q000276:immunology*
D015235:HLA-B Antigens; C103707:HLA-B57 antigen; C515083:KIR3DL1 protein, human; D054341:Receptors, KIR3DL1