Genetic polymorphism of NK receptors and their ligands in melanoma patients: prevalence of inhibitory over activating signals

Antitumor cytotoxicity of NK cells and T cells expressing NK-associated receptors is regulated by interaction between their cell surface killer immunoglobulin-like receptors (KIRs) and CD94/NKG2 heterodimers with MHC class I ligands on target cells. To test the hypothesis that KIR and/or HLA polymorphisms, and KIR/HLA combinations could contribute to the tumorigenesis, association studies were performed in 50 patients with malignant melanoma (MM) in different stages of disease and 54 controls. Our data showed that the frequency of inhibitory and activating KIR genes and KIR genotypes did not differ significantly between healthy individuals and melanoma patients. HLA haplotype distribution showed statistically significant increased frequencies of A*01-B*35-Cw*04 (0.069 vs 0.000; pc<0.05; OR=19.9), A*01-B*08-DRB1*03 (0.079 vs 0.019; pc<0.05; OR=4.5), and A*24-B*40-DRB1*11 (0.026 vs 0.000; pc<0.05; OR=7.1) in melanoma patients compared with healthy controls. Individuals homozygous for group 2 HLA-C ligands were less frequent in the patient group compared with the control cohort (12% vs 31.5%; p<0.017). In addition, we observed an increased frequency (88.0% vs 68.5%; p=0.017; OR=2.80) of KIR2DL2/2DL3 in combination with their group 1 HLA-C ligands, while the presence of these KIRs in the absence of the putative ligands was decreased (12.0% vs 31.5%; p=0.017) in the patient group. Furthermore, an increased frequency of activating KIR2DS1 in the absence of the putative HLA-C^Lys80 ligands was found in melanoma patients (16.0% vs 9.2%). In contrast, KIR2DS2 was absent in patients more often (38.0% vs 25.9%) when the presumptive HLA-C^Asn80 ligands were present. A slightly higher incidence of KIR3DL1 in combination with the less effective Bw4^Thr80 ligands was seen in patients with primary (20.8%) compared with metastatic (4.2%) disease. The data obtained in this study imply that there may not be a direct association between KIR gene content in the genome and the presence of malignant melanoma, or melanoma progression. However, some HLA haplotypes could be predisposing to MM in the Bulgarian population. Furthermore, distinct KIR/HLA ligand combinations may be relevant to the development of malignancy whereby inhibition overrides activation of NK cells and T cells expressing NK-associated receptors, which in turn might facilitate tumor escape and progression.     

Cutting edge: susceptibility to psoriatic arthritis: influence of activating killer Ig-like receptor genes in the absence of specific HLA-C alleles

NK cell activity is partially controlled through interactions between killer Ig-like receptors (KIR) on NK cells and their respective HLA class I ligands. Independent segregation of HLA and KIR genes, along with KIR specificity for particular HLA allotypes, raises the possibility that any given individual may express KIR molecules for which no ligand is present. Inhibitory receptor genes KIR2DL2/3 and KIR2DL1 were present in nearly all subjects sampled in this study, whereas their respective activating homologs, KIR2DS2 and KIR2DS1, are each present in about half of the subjects. In this work we report that subjects with activating KIR2DS1 and/or KIR2DS2 genes are susceptible to developing psoriatic arthritis, but only when HLA ligands for their homologous inhibitory receptors, KIR2DL1 and KIR2DL2/3, are missing. Absence of ligands for inhibitory KIRs could potentially lower the threshold for NK (and/or T) cell activation mediated through activating receptors, thereby contributing to pathogenesis of psoriatic arthritis.     

Role of the inhibitory KIR ligand HLA-Bw4 and HLA-C expression levels in the recognition of leukemic cells by Natural Killer cells

Transplantation of acute myeloid leukemia (AML) patients with grafts from related haploidentical donors has been shown to result in a potent graft-versus-leukemia effect. This effect is mediated by NK cells because of the lack of activation of inhibitory killer cell immunoglobulin-like receptors (KIRs) which recognize HLA-Bw4 and HLA-C alleles. However, conflicting results have been reported about the impact of KIR ligand mismatching on the outcome of unrelated HLA-mismatched hematopoietic stem cells transplants (HSCT) to leukemic patients. The interpretation of these conflicting results is hampered by the scant information about the level of expression of HLA class I alleles on leukemic cells, although this variable may affect the activation of inhibitory KIRs. Therefore in the present study, utilizing a large panel of human monoclonal antibodies we have measured the level of expression of HLA-A, -B and -C alleles on 20 B-chronic lymphoid leukemic (B-CLL) cell preparations, on 16 B-acute lymphoid leukemic (B-ALL) cell preparations and on 19 AML cell preparations. Comparison of the level of HLA class I antigen expression on leukemic cells and autologous normal T cells identified selective downregulation of HLA-A and HLA-B alleles on 15 and 14 of the 20 B-CLL, on 2 and 5 of the 16 B-ALL and on 7 and 11 of the 19 AML patients tested, respectively. Most interestingly HLA-C alleles were markedly downregulated on all three types of leukemic cells; the downregulation was most pronounced on AML cells. The potential functional relevance of these abnormalities is suggested by the dose-dependent enhancement of NK cell activation caused by coating the HLA-HLA-Bw4 epitope with monoclonal antibodies on leukemic cells which express NK cell activating ligands. Our results suggest that besides the HLA and KIR genotype, expression levels of KIR ligands on leukemic cells should be included among the criteria used to select the donor-recipient combinations for HSCT.     

Self-association of an activating natural killer cell receptor, KIR2DS1

As a major component of the innate immune system, natural killer cells are responsible for activating the cytolytic killing of certain pathogen-infected or tumor cells. The self-recognition of natural killer cells is achieved in part by the killer cell immunoglobulin-like receptors (KIRs) protein family. In the current study, using a suite of biophysical methods, we investigate the self-association of an activating KIR, KIR2DS1. This KIR is of particular interest because when in the presence of the HLA-Cw6 protein, KIR2DS1 becomes a major risk factor for psoriasis, an autoimmune chronic skin disease. Using circular dichroism spectroscopy, dynamic light scattering, and atomic force microscopy, we reveal that KIR2DS1 self-associates in a well-defined fashion. Our novel results on an activating KIR allow us to suggest a working model for the KIR2DS1- HLA class I molecular mechanism.     

KIR molecules: recent patents of interest for the diagnosis and treatment of several autoimmune diseases, chronic inflammation, and B-cell malignancies

There has been rapidly increasing interest in innate immunity in recent years. Natural killer (NK) cells are cytotoxic lymphocytes that constitute a major component of the innate immune system. NK cells are mainly modulated through different receptors and cytokines. The killer immunoglobulin-like receptors (KIRs) represent the largest category of NK cell receptors. KIR function is mainly regulated by binding both classical MHC I (human leukocyte antigen, HLA A, B and C) and also non-classical MHC. Some KIRs are specific to certain HLA subtypes. Questions about how the NK cells sense self-antigen, infection, and altered cells, and how a protective immune response can be induced are being answered at the molecular level. Research has revealed the central role of innate immunity in the pathogenesis of many autoimmune and inflammatory diseases, as well as B-cell malignancies, with the emergence of recent developments for KIR characterization, disease monitoring, and treatment. In this paper, we report three recent patents focused on KIR applications: the first one is targeted at the determination of the complex KIR haplotypes by using next generation sequencing; the second patent represents a practical approach for genotyping and treatment of the main KIR-related autoimmune and chronic inflammatory diseases; and the last patent describes the possible contributions of KIR to promising combination immunotherapies.     

MHC class I-independent recognition of NK-activating receptor KIR2DS4

Natural killer cells are capable of killing tumor and virus-infected cells. This killing is mediated primarily via the natural cytotoxicity receptors, including NKp46, NKp44, NKp30, and by the NKG2D receptor. Killer cell Ig-like receptors (KIRs) are mainly involved in inhibiting NK killing (inhibitory KIRs) via interaction with MHC class I molecules. Some KIRs, however, have been found to enhance NK killing when interacting with MHC class I molecules (activating KIRs). We have previously demonstrated that KIR2DS4, an activating KIR, recognizes the HLA-Cw4 protein. The interaction observed was weak and highly restricted to HLA-Cw4 only. These findings prompted us to check whether KIR2DS4 might have additional ligand(s). In this study, we show that KIR2DS4 is able to also interact with a non-class I MHC protein expressed on melanoma cell lines and on a primary melanoma. This interaction is shown to be both specific and functional. Importantly, site-directed mutagenesis analysis reveals that the amino acid residues involved in the recognition of this novel ligand are different from those interacting with HLA-Cw4. These results may shed new light on the function of activating KIRs and their relevance in NK biology.     

Influence of interleukin IL-2 and IL-12 + IL-18 on surface expression of immunoglobulin-like receptors KIR2DL1, KIR2DL2, and KIR3DL2 in natural killer cells

Natural killer (NK) cells express killer cell inhibitory receptors (KIRs) that recognize polymorphic class I MHC molecules. In the present study, we analyze the modulatory effect of IL-2 alone or a combination of IL-12 with IL-18 on surface expression of killer cell immunoglobulin-like receptors KIR2DL1, KIR2DL2, and KIR3DL2 in NK cells. Thus, it was found that IL-2 causes a significant increase in the proportion of cells with given studied receptors. Stimulation by a mixture of IL-12 and IL-18 caused significant increase in the fraction of cells with the KIR2DL1 and KIR2DL2, however no significant change in the percentage of cells with KIR3DL2 receptor on their surface was observed. The results of the study show the presence of KIRs on both resting and activated NK cells, this may suggest that KIRs have also an important role in the regulatory processes after activation of this subpopulation of cells.     

Exploring the Role of Killer Cell Immunoglobulin-Like Receptors and Their HLA Class I Ligands in Autoimmune Hepatitis

Background

Natural killer cells are involved in the complex mechanisms underlying autoimmune diseases but few studies have investigated their role in autoimmune hepatitis. Killer immunoglobulin-like receptors are key regulators of natural killer cell-mediated immune responses.

Methods and Findings

KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 114 patients diagnosed with type 1 autoimmune hepatitis and compared with a group of 221 healthy controls. HLA Class I and Class II antigen frequencies were compared to those of 551 healthy unrelated families representative of the Sardinian population. In our cohort, type 1 autoimmune hepatitis was strongly associated with the HLA-B18, Cw5, DR3 haplotype. The KIR2DS1 activating KIR gene and the high affinity HLA-C2 ligands were significantly higher in patients compared to controls. Patients also had a reduced frequency of HLA-Bw4 ligands for KIR3DL1 and HLA-C1 ligands for KIR2DL3. Age at onset was significantly associated with the KIR2DS1 activating gene but not with HLA-C1 or HLA-C2 ligand groups.

Conclusions

The activating KIR gene KIR2DS1 resulted to have an important predictive potential for early onset of type 1 autoimmune hepatitis. Additionally, the low frequency of the KIR-ligand combinations KIR3DL1/HLA-Bw4 and KIR2DL3/HLA-C1 coupled to the high frequency of the HLA-C2 high affinity ligands for KIR2DS1 could contribute to unwanted NK cell autoreactivity in AIH-1.     

KIR2DL2 enhances protective and detrimental HLA class I-mediated immunity in chronic viral infection

Killer cell immunoglobulin-like receptors (KIRs) influence both innate and adaptive immunity. But while the role of KIRs in NK-mediated innate immunity is well-documented, the impact of KIRs on the T cell response in human disease is not known. Here we test the hypothesis that an individual's KIR genotype affects the efficiency of their HLA class I-mediated antiviral immune response and the outcome of viral infection. We show that, in two unrelated viral infections, hepatitis C virus and human T lymphotropic virus type 1, possession of the KIR2DL2 gene enhanced both protective and detrimental HLA class I-restricted anti-viral immunity. These results reveal a novel role for inhibitory KIRs. We conclude that inhibitory KIRs, in synergy with T cells, are a major determinant of the outcome of persistent viral infection.     

The Structure of the Atypical Killer Cell Immunoglobulin-like Receptor,KIR2DL4

The engagement of natural killer cell immunoglobulin-like receptors (KIRs) with their target ligands, human leukocyte antigen (HLA) molecules, is a critical component of innate immunity. Structurally, KIRs typically have either two (D1-D2) or three (D0-D1-D2) extracellular immunoglobulin domains, with the D1 and D2 domain recognizing the α1 and α2 helices of HLA, respectively, whereas the D0 domain of the KIR3DLs binds a loop region flanking the α1 helix of the HLA molecule. KIR2DL4 is distinct from other KIRs (except KIR2DL5) in that it does not contain a D1 domain and instead has a D0-D2 arrangement. Functionally, KIR2DL4 is also atypical in that, unlike all other KIRs, KIR2DL4 has both activating and inhibitory signaling domains. Here, we determined the 2.8 Å crystal structure of the extracellular domains of KIR2DL4. Structurally, KIR2DL4 is reminiscent of other KIR2DL receptors, with the D0 and D2 adopting the C2-type immunoglobulin fold arranged with an acute elbow angle. However, KIR2DL4 self-associated via the D0 domain in a concentration-dependent manner and was observed as a tetramer in the crystal lattice by size exclusion chromatography, dynamic light scattering, analytical ultracentrifugation, and small angle x-ray scattering experiments. The assignment of residues in the D0 domain to forming the KIR2DL4 tetramer precludes an interaction with HLA akin to that observed for KIR3DL1. Accordingly, no interaction was observed to HLA by direct binding studies. Our data suggest that the unique functional properties of KIR2DL4 may be mediated by self-association of the receptor.     

Stimulatory killer Ig-like receptors modulate T cell activation through DAP12-dependent and DAP12-independent mechanisms

Stimulatory killer Ig-like receptors (KIRs) are expressed by various lymphocytes, including NK cells and subsets of T cells. In NK cells, KIRs associate with the adapter molecule KARAP/DAP12, which confers the ability to function as an independent activation unit. The function of KIRs and killer cell activating receptor-associated protein (KARAP)/DAP12 in T cells is unclear. By flow cytometry, we demonstrated that CD4+CD28null T cells heterogeneously express KIRs and/or KARAP/DAP12. In clones that lacked expression of KARAP/DAP12, the stimulatory KIR KIR2DS2 signaled through the JNK pathway, but did not activate the ERK pathway. However, in the presence of KARAP/DAP12, stimulation through KIR2DS2 led to phosphorylation of both JNK and ERK. Transfection experiments confirmed that KIR2DS2-mediated ERK phosphorylation was dependent on KARAP/DAP12. The differential signaling of KIR2DS2 through association with alternative adapter molecules resulted in differential regulation of cellular activity. In clones that lacked expression of KARAP/DAP12, stimulation of KIR2DS2 did not induce cytotoxicity. However, KIR2DS2 did augment suboptimal TCR stimulation, leading to enhanced IFN-gamma production. In clones that expressed KARAP/DAP12, KIR2DS2 directly activated both cytotoxicity and IFN-gamma production without the need for TCR-derived signals. The function of stimulatory KIRs in T cells is determined by the expression of the appropriate adapter molecule. Expression of KARAP/DAP12 is sufficient to convert a costimulatory KIR into a stimulatory molecule. These differing functions mediated by alternative signaling pathways have implications for the pathogenesis of diseases such as rheumatoid arthritis and acute coronary syndromes, in which aberrant expression of KIRs on T cells is frequently observed.     

Killer cell immunoglobulin-like receptor gene diversity in the Saudi population

Killer cell immunoglobulin-like receptors (KIRs) influence the outcome of haematopoetic stem cell transplantation by modulating the cytotoxic ability of natural killer (NK) cells and a subset of T cells. KIRs are also highly polymorphic and could therefore be good population genetic markers, much like their human leukocyte antigen (HLA) ligands. This study represents the first report on distribution of 16 KIR genes in 162 unrelated healthy Saudi individuals. All the 16 KIR genes were observed in the studied population and the four framework genes (KIR2DL4, 3DL2, 3DL3 and 3DP1) were present in all individuals. Forty- one distinct KIR profiles were expressed in our population, 11 of which had not been previously described in other populations including the Middle Eastern population. AA1, the most common genotypic profile was observed at a frequency of 26.5%. The group A haplotype was more frequent (53%) in the Saudi population compared to the group B haplotype (47%). The pattern of the inhibitory KIR/HLA ligands were also analyzed and 52.3% of the Saudi population was found to express two pairs of the inhibitory KIR/HLA-C. The KIR gene frequencies suggests that the Saudi population shares common general features with the Middle Eastern and other populations, but still has its own unique frequencies of several KIR loci.     

Cutting edge: resistance to HIV-1 infection among African female sex workers is associated with inhibitory KIR in the absence of their HLA ligands

NK cells are regulated in part by killer Ig-like receptors (KIR) that interact with HLA molecules on potential target cells. KIR and HLA loci are highly polymorphic and certain KIR/HLA combinations were found to protect against HIV disease progression. We show in this study that KIR/HLA interactions also influence resistance to HIV transmission. HIV-exposed but seronegative female sex workers in Abidjan, C?te d'Ivoire, frequently possessed inhibitory KIR genes in the absence of their cognate HLA genes: KIR2DL2/KIR2DL3 heterozygosity in the absence of HLA-C1 and KIR3DL1 homozygosity in the absence of HLA-Bw4. HIV-seropositive female sex workers were characterized by corresponding inhibitory KIR/HLA pairings: KIR2DL3 homozygosity together with HLA-C1 and a trend toward KIR3DL1/HLA-Bw4 homozygosity. Absence of ligands for inhibitory KIR could lower the threshold for NK cell activation. In addition, exposed seronegatives more frequently possessed AB KIR genotypes, which contain more activating KIR. The data support an important role for NK cells and KIR/HLA interactions in antiviral immunity.     

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The antiviral action of natural killer (NK) cells is regulated by a wide repertoire of germ-line encoded membrane receptors which recognize the expression of certain self-molecules on target cells. Among the receptors, killer cell immunoglobulin-like receptor (KIR) which recognizes the expression of human leukocyte antigen (HLA) class I has a predominant role in regulating the effector functions of NK cells, particularly in viral infections. We studied a total of 128 hepatitis B virus (HBV) patients (15 acute, 43 asymptomatic, 27 chronic and 43 with other liver diseases) while attending the Department of Medical Gastroenterology, Government Rajaji Hospital, Madurai, India, and 128 ethnic matched control to find the association between the KIR : HLA genes and differential manifestations of HBV. KIR and its ligand HLA polymorphism were identified by DNA-PCR methods. The activatory receptor KIR-2DS1 was significantly elevated in various disease categories, namely asymptomatic, chronic and other HBV, except acute HBV infection. Whereas, KIR 2DS3 in acute and chronic patients and KIR 2DS5 and 3DS1 in asymptomatic individuals. Among various KIR–HLA combinations, homozygous 2DS2:C1 and individuals with 3DSI:BW4 (OR = 3.23, CI = 1.55–6.7, Pc = 0.02) are associated with HBV asymptomatism, while most of the two domain inhibitory receptors with their ligands showed significant risk in other liver diseases. Further, KIR3DL1 : HLA Bw4Iso80 (OR = 3.89, 95% CI = 1.58–9.55, Pc = 0.004) is related with higher risk for asymptomatic infection when compared with chronic HBV. Thus, the select KIR : HLA alleles and combinations seem to direct the NK cell activities and immune response in different directions resulting in varied symptoms and manifestations in the subgroups of HBV-infected patients studied.     

Determinants of antileukemia effects of allogeneic NK cells

In HLA-nonidentical bone marrow transplantation, we studied the characteristics of donor NK cells, recipient leukemia cells, and the cytokine environment that predict the antileukemia effects of allogeneic NK cells. We found that the risk of relapse in pediatric patients with hematologic malignancies was best predicted by a model taking into consideration the presence of inhibitory killer cell Ig-like receptors (KIRs) on the donor's NK cells and the absence of corresponding KIR ligand in the recipient's HLA repertoire (a receptor-ligand model). The risk of relapse was prognosticated less precisely by the Perugia donor-recipient KIR ligand-ligand mismatch model or by a natural cytotoxicity model. In contrast to the ligand-ligand model, we found that the new receptor-ligand model was accurate when analysis was applied to patients with lymphoid malignancy. These findings corroborate our observations that the recipient's KIR repertoire, which was derived from highly purified, HLA-disparate CD34+ cells, resumed a donor-specific pattern within 3 mo of transplantation, but did not correlate evidently with the donor or recipient ligand repertoire. In an in vitro assay and an in vivo mouse model, human NK cell cytotoxicity toward human leukemia cells with 11q23 chromosomal rearrangement increased with the number of receptor-ligand mismatch pairs or prestimulation with IL-12 and IL-18. These findings provide new insights into the determinants of antileukemia effects of allogeneic NK cells and therapeutic strategies.     

Polymorphisms of killer immunoglobulin-like receptors (KIRs) and HLA ligands in northeastern Thais

Killer cell immunoglobulin-like receptors (KIRs) are cell surface receptors on natural killer (NK) cells and subsets of T cells. The functions of NK cells are partly regulated by interactions between KIRs and HLA ligands on target cells. In this study, the presence or absence of 17 KIR genes and their known HLA ligands have been investigated in 235 unrelated individuals living in northeastern Thailand (NET). Subtypes of KIR2DS4 including full length (KIR2DS4F) and deleted forms (KIR2DS4D) have also been determined. Framework genes (KIR2DL4, 3DL2, 3DL3, and 3DP1) were found in all individuals and KIR genes belonging to the A haplotype (KIR2DL1, 2DL3, 3DL1, and 2DS4) were present in more than 90 % of NET. KIR2DS4D (61.7 %) was more common than KIR2DS4F (52.8 %). A total of 33 different KIR genotypes were observed. Of these, three new genotypes were identified. The most common genotype (AA) was observed in 35.7 % of NET, and HLA-C alleles bearing the C1 epitope (HLA-C1) had the highest frequency (97 %). All individuals had at least one inhibitory KIR and its corresponding HLA ligand; 40.9 % of NET had three pairs of receptor–ligand combinations, and 18.3 % had all three receptor–ligand combinations of KIR2DL3+C1, 3DL1+Bw4, and 3DL2+A11. Surprisingly, the patterns of KIR gene frequencies in NET are more similar to those of Caucasians than Japanese, Korean, and Chinese. This is the first report on complete analysis of KIR and known HLA ligands in Thais. These data provide basic knowledge on KIR for further studies on disease associations and transplantation in northeastern Thais.     

Human-specific evolution of killer cell immunoglobulin-like receptor recognition of major histocompatibility complex class I molecules

In placental mammals, natural killer (NK) cells are a population of lymphocytes that make unique contributions to immune defence and reproduction, functions essential for survival of individuals, populations and species. Modulating these functions are conserved and variable NK-cell receptors that recognize epitopes of major histocompatibility complex (MHC) class I molecules. In humans, for example, recognition of human leucocyte antigen (HLA)-E by the CD94:NKG2A receptor is conserved, whereas recognition of HLA-A, B and C by the killer cell immunoglobulin-like receptors (KIRs) is diversified. Competing demands of the immune and reproductive systems, and of T-cell and NK-cell immunity-combined with the segregation on different chromosomes of variable NK-cell receptors and their MHC class I ligands-drive an unusually rapid evolution that has resulted in unprecedented levels of species specificity, as first appreciated from comparison of mice and humans. Counterparts to human KIR are present only in simian primates. Observed in these species is the coevolution of KIR and the four MHC class I epitopes to which human KIR recognition is restricted. Unique to hominids is the emergence of the MHC-C locus as a supplier of specialized and superior ligands for KIR. This evolutionary trend is most highly elaborated in the chimpanzee. Unique to the human KIR locus are two groups of KIR haplotypes that are present in all human populations and subject to balancing selection. Group A KIR haplotypes resemble chimpanzee KIR haplotypes and are enriched for genes encoding KIR that bind HLA class I, whereas group B KIR haplotypes are enriched for genes encoding receptors with diminished capacity to bind HLA class I. Correlating with their balance in human populations, B haplotypes favour reproductive success, whereas A haplotypes favour successful immune defence. Evolution of the B KIR haplotypes is thus unique to the human species.     

Low CD4+ T cell counts among African HIV-1 infected subjects with group B KIR haplotypes in the absence of specific inhibitory KIR ligands

Natural killer (NK) cells are regulated by interactions between polymorphic killer immunoglobulin-like receptors (KIR) and human leukocyte antigens (HLA). Genotypic combinations of KIR3DS1/L1 and HLA Bw4-80I were previously shown to influence HIV-1 disease progression, however other KIR genes have not been well studied. In this study, we analyzed the influence of all activating and inhibitory KIR, in association with the known HLA inhibitory KIR ligands, on markers of disease progression in a West African population of therapy-naïve HIV-1 infected subjects. We observed a significant association between carriage of a group B KIR haplotype and lower CD4+ T cell counts, with an additional effect for KIR3DS1 within the frame of this haplotype. In contrast, we found that individuals carrying genes for the inhibitory KIR ligands HLA-Bw4 as well as HLA-C1 showed significantly higher CD4+ T cell counts. These associations were independent from the viral load and from individual HIV-1 protective HLA alleles. Our data suggest that group B KIR haplotypes and lack of specific inhibitory KIR ligand genes, genotypes considered to favor NK cell activation, are predictive of HIV-1 disease progression.