Of the main types of NK inhibitory receptors, the killer inhibitory receptor (KIR) family exhibits a restricted pattern of expression and Fluorouracil interact with only a limited subset of MHC class I ligands [83,84]. Nevertheless, inheritance of specific KIR alleles has profound implications for individual susceptibility to infectious diseases [85,86]. As shown in Table 3, the KIR3DL1/S1 locus has been associated with both slow progression to AIDS and resistance to HIV-1 infection. Inheritance of protective KIR3DL1high receptor alleles that lead to high cell surface expression and greater NK licensing were

observed to be over-represented in a high-risk cohort of HESN i.v. drug users from Montreal compared to HIV-1-infected subjects from the same geographic area (68·3% compared to 57·0%, respectively) [28]. KIR3DS1, an activating allele of the same KIR3DL1 locus, was also identified to be enriched in HESN subjects within the same Montreal Wnt inhibitor cohort (13·8% compared to 5·3%, respectively) [17]. A smaller study of high-risk HESN female sex workers

from the Ivory Coast found no such association [2], although this latter finding is limited by the low frequency of the KIR3DS1 allele in African populations compared to Caucasians [87]. In support of a functional link with these protective alleles, NK cells expressing KIR3DS1 have been shown to produce more interferon (IFN)-γ[88] and mediate stronger inhibition of HIV-1 replication [89]. Additional evidence for the protective role of

NK cells in resistance to HIV-1 stems from a genetic study linking variants in non-classical MHC class I HLA-E and HLA-G molecules with reduced susceptibility to heterosexual acquisition of HIV-1 Non-specific serine/threonine protein kinase [90]. Among the NK inhibitory receptors, the CD94/NKG2A receptor complex is unique in that it interacts specifically with the non-classical MHC protein, HLA-E, which presents leader peptides from the other classical MHC class I HLA-A, B, C molecules [83,84]. Inheritance of the HLA-E*0103 genetic variant, which leads to increased surface expression of HLA-E proteins and heightened NK surveillance of virally infected cells that down-regulate MHC class 1 proteins, was associated with a decreased risk of human immunodeficiency virus 1 (HIV-1) infection in Zimbabwean women [90]. Similarly, women carrying the HLA-G*0105N genotype, resulting in a null HLA-G inhibitory protein that cannot inhibit NK cells, also have a significantly decreased risk of HIV-1 infection [90]. While these genetic data suggest that NK stimulatory alleles are associated with protection from infection in some HESN subjects, a good number of HESN subjects lack these protective alleles.