Research Article: HIV Protective KIR3DL1/S1-HLA-B Genotypes Influence NK Cell-Mediated Inhibition of HIV Replication in Autologous CD4 Targets

Date Published: January 16, 2014

Publisher: Public Library of Science

Author(s): Rujun Song, Irene Lisovsky, Bertrand Lebouché, Jean-Pierre Routy, Julie Bruneau, Nicole F. Bernard, Ronald C. Desrosiers.


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.

Partial Text

NK cells function in innate immune responses to transformed and virally infected cells. They can exert their anti-viral effects soon after encountering infected targets without prior sensitization [1]. NK cell function is determined by signals from activating and inhibitory cell surface receptors, which include Killer Immunoglobulin-like Receptors (KIR) [2]. Among these are inhibitory KIR3DL1 (3DL1) and activating KIR3DS1 (3DS1) receptors, which are encoded by alleles at the same KIR3DL1/S1 locus [3]. 3DL1 receptors can be classified into those expressed on NK cell surfaces at high levels (*h) low levels (*l) or *004, which is only transiently expressed [4]–[7]. 3DL1 homozygous genotypes can be dichotomized into *h/*y and *l/*x groups where *h/*y genotypes encode receptors expressed on the NK cell surface at higher levels than those encoded by *l/*x genotypes [6].

In this report we showed that NK cells cultured with autologous iCD4 cells limit the spread of HIV resulting in a lower frequency of HIV iCD4 cells and lower levels of viral replication compared to iCD4 cells cultured alone. Contact between NK and iCD4 cells stimulates NK cells to produce soluble factors, which suppress HIV replication in a non-contact dependent fashion. NK cells activated by autologous iCD4 cells in the presence of IL-2 secrete CC-chemokines at higher levels than when only IL-2 is present. CC-chemokine secretion is responsible, at least in part, for the inhibitory effect of NK cells on viral replication. KIR/HLA genotype influences the potency of inhibition of viral replication. We showed that NK cells from *h/*y+B*57 and 3DS1+*80I carriers, genotypes associated slower time to AIDS and VL control, inhibited HIV replication more potently than did those from Bw6hmz and carriers of the *l/*x+B*57genotype. NK cells, and in particular the 3DL1+ subset of NK cells, from carriers of the *h/*y+B*57 genotype secrete higher levels of CC-chemokines than those from Bw6hmz and *l/*x+B*57 subjects.




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