Article

Differential natural killer cell–mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes

Partners AIDS Research Center and Infectious Disease Unit, Massachusetts General Hospital and Division of AIDS, Harvard Medical School, Boston, MA 02129, USA.
Journal of Experimental Medicine (Impact Factor: 13.91). 12/2007; 204(12):3027-36. DOI: 10.1084/jem.20070695
Source: PubMed

ABSTRACT Decline of peak viremia during acute HIV-1 infection occurs before the development of vigorous adaptive immunity, and the level of decline correlates inversely with the rate of AIDS progression, implicating a potential role for the innate immune response in determining disease outcome. The combined expression of an activating natural killer (NK) cell receptor, the killer immunoglobulin-like receptor (KIR) 3DS1, and its presumed ligand, human leukocyte antigen (HLA)-B Bw4-80I, has been associated in epidemiological studies with a slow progression to AIDS. We examined the functional ability of NK cells to differentially control HIV-1 replication in vitro based on their KIR and HLA types. NK cells expressing KIR3DS1 showed strong, significant dose- and cell contact-dependent inhibition of HIV-1 replication in target cells expressing HLA-B Bw4-80I compared with NK cells that did not express KIR3DS1. Furthermore, KIR3DS1+ NK cells and NKLs were preferentially activated, and lysed HIV-1 infected target cells in an HLA-B Bw4-80I-dependent manner. These data provide the first functional evidence that variation at the KIR locus influences the effectiveness of NK cell activity in the containment of viral replication.

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Available from: Todd M Allen, Aug 20, 2015
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    • "NK cells sense this loss (loss of self) through KIR and respond vigorously by directly killing the infected or malignant target cells or by releasing cytokines which recruit other immune cells [12] [13]. Some KIR genes have been associated with increased susceptibility or resistance to infectious, autoimmune and metabolic diseases [14] [15] [16] [17] [18] [19]. NK cells were initially identified by their ability to spontaneously kill tumour cells without prior sensitisation [20] [21] [22]. "
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    • "Studies of virus specific T-and B-cell responses have been much at the center of these efforts, and have linked several key features of the adaptive immune response with relative viral control in vivo [67] [68] [69] [70] [71] [72] [73] [74] [75] [76]; Figure 3). More recent studies have also revealed potentially crucial factors of the innate immune system in this control, although in some cases, the mechanistic details remain to be defined and may involve virus capture and transfer as well as immune modulation by dendritic cells [77] [78] [79] [80] [81] [82]. Common to many of these correlative ex vivo studies or in vitro assays is that they often cannot discriminate between the cause and effects of controlled HIV infection, leaving the field still in the obscure what factors directly and actively mediate anti-viral effects. "
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    • "In contrast, the natural ligand of KIR3DS1 has yet to be identified . Recent genetic and functional studies have suggested that certain HLA-Bw4 molecules containing an isoleucine in position 80 (HLA-Bw4-I80) are a potential putative ligand for KIR3DS1 (Martin et al., 2002; Alter et al., 2007, 2009). However, despite several attempts by different groups, direct interactions between KIR3DS1 and HLA-Bw4 molecules have not yet been demonstrated (Carr et al., 2007; Gillespie et al., 2007; O'Connor et al., 2007), with the exception of one report by Li et al. (2010) suggesting interactions between KIR3DS1 and the HLA-Bw4-T80 allotype "
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    ABSTRACT: The function of natural killer (NK) cells is controlled by several activating and inhibitory receptors, including the family of killer-immunoglobulin-like receptors (KIRs). One distinctive feature of KIRs is the extensive number of various haplotypes generated by the gene content within the KIR gene locus as well as by highly polymorphic members of the KIR gene family, namely KIR3DL1/S1. Within the KIR3DL1/S1 gene locus, KIR3DS1 represents a conserved allelic variant and displays other unique features in comparison to the highly polymorphic KIR3DL1 allele. KIR3DS1 is present in all human populations and belongs to the KIR haplotype group B. KIR3DS1 encodes for an activating receptor featuring the characteristic short cytoplasmic tail and a positively charged residue within the transmembrane domain, which allows recruitment of the ITAM-bearing adaptor molecule DAP12. Although HLA class I molecules are thought to represent natural KIR ligands, and HLA-Bw4 molecules serve as ligands for KIR3DL1, the ligand for KIR3DS1 still needs to be identified. Despite the lack of formal evidence for an interaction of KIR3DS1 with HLA-Bw4-I80 or any other HLA class I subtype to date, a growing number of associations between the presence of KIR3DS1 and the outcome of viral infections have been described. Especially, the potential protective role of KIR3DS1 in combination with HLA-Bw4-I80 in the context of HIV-1 infection has been studied intensively. In addition, a number of recent studies have associated the presence or absence of KIR3DS1 with the occurrence and outcome of some malignancies, autoimmune diseases, and graft-versus-host disease (GVHD). In this review, we summarize the present knowledge regarding the characteristics of KIRD3S1 and discuss its role in various human diseases.
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