Natural Killer Cells from HIV Infected Slow Progressors Who Carry the Protective HLA-B*27 Allele and Inhibitory KIR3DL1 Receptors Have Elevated Poly-Functional Potential Compared to Bw6 Homozygotes

HIV Infection in the Era of Highly Active Antiretroviral Treatment and Some of Its Associated Complications 194Activation of NK cells is regulated through the integration of signals from a number of activating and inhibitory receptors (Lanier 2005).Many of the inhibitory receptors use major histocompatibility complex (MHC) class I or class I-like proteins as their ligands (Lanier 2005).The interaction between inhibitory NK receptors and their ligands during NK cell development is important in educating these cells for subsequent function and for avoiding reactivity to normal cells expressing self MHC class I (Kim et al. 1969;Anfossi et al. 2006).In humans one large family of NK receptors are encoded by the Killer Immunoglobulin-like Receptors (KIR) region that maps to chromosome 19q13.4(Lanier 2005).The most polymorphic locus among the KIR region genes is KIR3DL1, which encodes both inhibitory KIR3DL1 (3DL1) and activating KIR3DS1 (3DS1) alleles (Norman et al. 2007).3DL1 alleles can be further classified according to their expression levels on the cell surface into high (*h), low/intermediate (*l) and null (*004) (not cell surface expressed) alleles (Yawata et al. 2006;Norman et al. 2007;Gardiner et al. 2001;Pando et al. 2003).Genotypes homozygous for 3DL1 can be divided into 2 groups: *h/*y, where *y can be either another *h allele or *004 with no *l alleles, and *l/*x, where *x can be an *l, *x or *004 allele (Martin et al. 2007).3DL1 receptors recognize a subset of MHC class I HLA-B molecules known as Bw4.HLA-Bw4 differ from the remaining HLA-Bw6 antigens encoded at this locus, which do not interact with 3DL1, in the amino acids present between positions 77 and 83 of the HLA heavy chain (Wan et al. 1986).Bw4 allotypes with isoleucine at position 80 (Bw4*80I) have been reported to be better ligands for many of the 3DL1 alleles (Cella et al. 1994).However, there is evidence that Bw4 antigens with threonine at position 80 (Bw4*80T), particularly HLA-B*2705, interact strongly with certain 3DL1 receptors (Luque et al. 1996).Epidemiological studies have reported that several KIR/HLA combinations are associated with slower progression to AIDS and suppression of viral load (VL) (Martin et al. 2007).Compared to Bw6 homozygotes (hmz) the 3DL1/HLA-B combination having the most potent influence on slowing time to AIDS and VL control is 3DL1*h/*y with HLA-B*57 (*h/*y+B*57) (Martin et al. 2007).Previous work from our group showed that NK cells from individuals carrying this genotype combination demonstrated higher functional potential than those from carriers of either the NK receptor genotype or HLA-B*57 alone or from Bw6 hmz (Boulet et al. 2010).In these studies functional potential was defined as the percent contribution of NK cells secreting interferon-γ (IFNγ) and tumor necrosis factor-α (TNF-α) and expressing CD107a, a marker of degranulation to the total response to stimulation with the HLA devoid K562 cell line.Furthermore, NK cells from carriers of *h/*y+B*57 had higher functional potential than carriers of 3DL1*h/*y with other Bw4 alleles (Boulet et al. 2010).HLA-B*57 is an HLA antigen considered to be protective in the context of HIV infection (Kaslow, Dorak, and Tang 2005;Altfeld et al. 2003;Leslie et al. 2004;Carrington, Martin, and van Bergen 2008).While the protective effect conferred by HLA-B*57 is mediated at least in part through CD8 + T cell recognition of HIV epitopes restricted by this antigen, epidemiological studies and our results support the possibility that HLA-B*57's protective effect may also be mediated through its ability to educate NK cells for superior functional potential (Martin et al. 2002;Martin et al. 2007;Leslie et al. 2004;Miura et al. 2009;Leslie et al. 2005).Murine models have shown using single MHC class I transgenic mice that MHC class I molecules can differ from each other in the potency of their NK education signals, which directly translates into activation potency upon encountering cells lacking that MHC ligand (Brodin, Karre, and Hoglund 2009).Since NK cells from *h/*y+B*57 carriers had higher functional potential than carriers of 3DL1*h/*y with other Bw4 alleles, HLA-B*57 may be an www.intechopen.com

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