Song Rujun, Lisovsky Irene, Lebouché Bertrand, Routy Jean-Pierre, Bruneau Julie, Bernard Nicole F
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 ; Department of Family Medicine, McGill University, Montreal, Quebec, Canada.
PLoS Pathog. 2014 Jan;10(1):e1003867. doi: 10.1371/journal.ppat.1003867. Epub 2014 Jan 16.
Carriage of the genetic combination encoding a high expression inhibitory Killer Immunoglobulin-like Receptor (KIR)3DL1 with its ligand, HLA-B*57 (*h/y+B57) 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+B57 carriers receive potent educational signals through HLA-B57 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+B57, a low expression KIR3DL1 genotype with HLA-B57 termed *l/x+B57, a genotype designated 3DS1+*80I and Bw6hmz. NK cells from *h/y+B57 carriers, like those from 3DS1+*80I subjects, inhibited HIV replication in autologous iCD4 cells better than those from Bw6hmz and *l/x+B57 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+B57 and 3DS1+*80I carriers produced higher levels of CC-chemokines than those from Bw6hmz or *l/x+B57 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.
携带编码高表达抑制性杀伤细胞免疫球蛋白样受体（KIR）3DL1及其配体HLA - B57（h/y + B57）的基因组合，与艾滋病进展时间较慢以及HIV病毒载量控制较好相关，这优于Bw6纯合子（Bw6hmz）。来自h/y + B57携带者的自然杀伤（NK）细胞通过HLA - B57与KIR3DL1的结合接受有效的教育信号，从而具有较高的功能潜力。来自Bw6hmz的NK细胞不会通过KIR3DL1接受教育，因为Bw6抗原不会与这种抑制性受体相互作用。为了更好地理解KIR/HLA组合对NK细胞介导的抗病毒活性的影响，我们通过在有和没有NK细胞的情况下纵向评估p24阳性CD4靶标的频率和HIV p24的上清液水平，来测量NK细胞对自体感染的CD4（iCD4）细胞中HIV复制的介导抑制作用。对47名未感染HIV的受试者进行了研究，包括h/y + B57携带者、一种低表达KIR3DL1基因型与HLA - B57的组合（称为l/x + B57）、一种指定为3DS1 + 80I的基因型以及Bw6hmz。来自h/y + B57携带者的NK细胞，与来自3DS1 + 80I受试者的NK细胞一样，在自体iCD4细胞中对HIV复制的抑制作用优于来自Bw6hmz和l/x + B57携带者的NK细胞。NK细胞与iCD4细胞之间的细胞接触激活了NK细胞，使其通过分泌CC趋化因子以非接触依赖的方式抑制病毒复制。来自h/y + B57和3DS1 + 80I携带者的iCD4刺激的NK细胞产生的CC趋化因子水平高于来自Bw6hmz或l/x + B57携带者的NK细胞。KIR3DL1(+)的NK细胞产生的CC趋化因子水平高于KIR3DL1(-)的NK细胞。我们得出结论，NK细胞介导的对自体iCD4细胞中病毒复制的抑制部分归因于分泌的CC趋化因子在HIV进入新靶标水平的阻断。
