KIR3DS1 was the first KIR to be associated with the outcome of a viral infection, namely, delayed HIV disease progression in patients with certain HLA B alleles. Since then, it has been extensively linked to other viral infections, autoimmune disorders, cancer development/clearance, and transplantation outcomes. Consequently, it has become one of the most studied KIRs. KIR3DS1 is an activating receptor that stimulates cytotoxicity and IFN-gamma production in NK cells. It is encoded in the KIR3DL1/KIR3DS1 gene locus, a unique KIR locus because it encodes for functionally divergent alleles. Remarkably, while sharing 95% homology in their extracellular domain, KIR3DS1 and its inhibitory counterpart KIR3DL1 have different ligand binding profiles. KIR3DL1 has conclusively been shown to bind HLA A and B proteins with a Bw4 motif. However, attempts to identify a KIR3DS1 ligand by various groups have repeatedly failed. The goal of this study was to identify ligands of KIR3DS1 and thus uncover the mechanistic basis for its influence in various human diseases. To this end, in collaboration with Dr. Marcus Altfeld at the Ragon Institute, we employed soluble receptor binding assays and cell-based functional assays to comprehensively screen HLA class I proteins in two biologically relevant conformation states: as HLA class I complexes, which are folded heavy chains bound to B2 microglobulin (B2m) and peptide, and as HLA class I open conformers (OCs), which are HLA class I heavy chains without bound B2m or peptide. We identified that HLA F OCs are high-affinity ligands of KIR3DS1, and also lower affinity ligands of the inhibitory receptors KIR3DL1 and KIR3DL2. We also demonstrated that this interaction is of functional relevance using reporter cell lines, primary KIR3DS1+ NK cells, and primary CD4+ T cells, providing an explanation for the widespread influence of KIR3DS1 in human disease. This newly identified KIR3DS1+HLA-F axis has many similarities to the well-known stress-induced NKG2D-MIC-A/B axis, even in the context of HIV-1 infection. Although it is less well-studied, HLA-F bears unique and distinguishing characteristics that separates it from all other HLA class I genes. In agreement with previous studies, our data show that HLA-F OCs are expressed on the surface of activated CD4+ T cells. Additionally, HIV-1 infection of CD4+ T cells increased transcription of HLA-F but reduced KIR3DS1 ligand expression, particularly in late-infected cells, which might suggest the employment of an immune-evasion strategy, potentially through the downregulation of HLA F by HIV1 accessory proteins, similar to what has been described for HIV1 Nef for HLA A and HLA B and NKG2D ligands including MIC A. KIR3DS1/HLA F interactions between NK cells and pathologically altered target cells would incur the well-known innate function of NK cells to recognize and eliminate target cells expressing stressed self ligands. This is supported by our in vitro co-culture assay, which showed that NK cells singly expressing KIR3DS1 are more effective at suppressing HIV1 replication in autologous CD4+ T cells as compared to KIR3DS1 negative NK cells. In addition, our data show that KIR3DS1/HLA-F interactions elicit NK cell production of antiviral and pro-inflammatory cytokines such as IFNgamma, TNF, and MIP1Beta, which would have pleiotropic effects on immune responses. Furthermore, KIR3DS1/HLA F interactions between NK cells and activated CD4+ T cells would also suggest a means of NK cell-mediated adaptive immune regulation. Thus, KIR3DS1 recognition of HLA F OCs expressed on activated immune cells and/or infected target cells provides a mechanistic link between KIR3DS1 and HIV1 disease progression, and will also have relevance for the pathogenesis of other infectious diseases, autoimmune disorders, and tumor immune-surveillance. HLA-B*57 is well known to associate with control of HIV, an observation that has largely been attributed to enhanced CD8+ T cell responses to infected cells. There is, however, extensive heterogeneity in control of HIV among B*57+ individuals, where many progress as rapidly to AIDS as B*57 negative subjects, indicating that there are other factors contributing to B*57 protection. We sought to identify genetic modifiers of B*57 using whole genome sequencing (WGS) of 100 HIV controllers and 100 non-controllers, all carrying one or two copies of HLA-B*57. A polymorphism (rs643347A/G) located in the KIR3DL1 gene that encodes an isoleucine to valine substitution at amino acid 47 (I47V) was the only variant to reach genome wide significance, with valine conferring protection. An independent B*57+ cohort in which KIR3DL1 was typed confirmed the protective effect of KIR3DL1 47V. The protective effect replicated across multiple alternative outcome measures, including longitudinal values for both mean viremia and CD4+ Tcell counts. Positions 2, 47, and 54, which are in near perfect linkage disequilibrium (LD) with one another, associated most strongly with HIV control relative to all other KIR3DL1 amino acid variants. Moreover, the effect was confined specifically to B*57:01, with no effect seen for the closely related B*57:03. These data implicate KIR3DL1 in modifying the effect of B*57:01 in control of HIV and provide insight into the factors that underlie the differential control of HIV across B*57+ subjects. We are now performing functional analyses in order to define the underlying mechanism(s) that explain the genetic data. Patients with common variable immune deficiency (CVID) display hypogammaglobulinemia, blunted antibody responses to bacterial polysaccharides, and recurrent sinopulmonary infections. Major histocompatibility complex (MHC) haplotypes associated with some autoimmune disorders are linked to CVID. However, inheritance of these haplotypes is insufficient for CVID development. We postulated a role for other immunogenetic factors that might interact with the MHC such as KIR. We tested whether KIR/HLA genotypes influence the risk of CVID in patients from the Southeastern USA. We genotyped KIR and HLA, and performed an ImmunoChip Assay on 175 affected individuals and on 72 spousal controls without evidence of immune dysfunction. We used logistic regression to estimate odds ratios and corresponding confidence intervals (CI). KIR genes associated with disease risk included activating KIR2DS1 (OR=1.45; P=0.03) and KIR3DS1 (OR = 1.54; P=0.01) and inhibitory KIR2DL5 (OR=1.43; P=0.04), (Figure 1). All three genes are found on KIR B haplotypes in linkage disequilibrium (6). KIR2DL5 has previously been shown to confer susceptibility to the autoimmune disease psoriasis vulgaris (PV), and KIR2DS1 is associated with both PV and psoriatic arthritis (PsA). Analysis of KIR/HLA receptor-ligand combinations on disease risk indicated an increased risk with the compound genotype KIR3DS1+HLA-Bw4. KIR2DL1+HLA-C group 2 was protective (OR=0.58, P=0.002), while homozygosity for KIR2DL3+HLA-C group 1 was associated with increased CHI risk (OR=1.88, P=0.002). Overall, the data suggest that CVID risk increases in patients where NK cell activation can be facilitated. The mechanism by which KIR alleles could influence the development of CVID is unknown. Upon activation, NK cells become cytotoxic, produce inflammatory cytokines and interact with dendritic cells and macrophages. It is possible that enhanced NK activation could be advantageous for patients exposed to infection, but detrimental in a disease such as CVID where enhancement of an inflammatory response to an antigen, either environmental or pathogen derived, could set up a regulatory cascade that results in a variable block in B cell development and antibody production.