Abstract
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.
Highlights
Natural Killer (NK) cells function in innate immune responses to transformed and virally infected cells
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 [4,5,6,7]. 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]
NK cell activation levels depend on the interaction of cell surface receptors on NK cells with the molecules they recognize on neighboring target cells
Summary
NK cells function in innate immune responses to transformed and virally infected cells. Epidemiological studies have found that several 3DL1 homozygous genotypes co-carried with a subset of HLA-B and –A alleles belonging to the HLA-Bw4 group are associated with slower time to AIDS and viral load (VL) control [7]. The genotype combinations that confers the highest degree of protection in terms of time to AIDS and VL control is 3DL1*h/*y co-carried with HLA-B*57 (*h/*y+B*57) [7]. Subjects with this combined genotype are more frequent among HIV Exposed Seronegative (HESN) than HIV susceptible individuals, implicating carriage of this genotype combination in reducing HIV infection risk [9]. NK cells from carriers of *h/ *y+B*57 have more potent NK cell functional potential as defined by HLA-null cell induced secretion of IFN-c and TNF-a and expression of CD107a, a marker for degranulation, than those
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