Role of KIR3DS1 in Human Diseases

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

Crippling HIV one mutation at a time

Accumulating data suggest that not all human immunodeficiency virus (HIV)-1–specific immune responses are equally effective at controlling HIV-1 replication. A new study now demonstrates that multiple immune-driven sequence polymorphisms in the highly conserved HIV-1 Gag region of transmitted viruses are associated with reduced viral replication in newly infected humans. These data suggest that targeting these and other conserved viral regions may be the key to developing an effective HIV-1 vaccine

Enhanced immune activation linked to endotoxemia in HIV-1 seronegative MSM

This study assessed cellular and soluble markers of immune activation in HIV-1 seronegative MSM. MSM immune profiles were characterized by an increased expression of CD57 on T cells and endotoxemia. Endotoxin presence was linked to recent high-risk exposure and associated with elevated cytokine levels and decreased CD4+/CD8+ T cell ratios. Taken together, these data show elevated levels of inflammation linked to periods of endotoxemia resulting in a significantly different immune phenotype in a subset of MSM at a high risk of HIV-1 acquisition.National Institutes of Health (U.S.) (Grant P01 AI074415

Fully Differentiated HIV-1 Specific CD8+ T Effector Cells are More Frequently Detectable in Controlled than in Progressive HIV-1 Infection

Background: CD8+ T cells impact control of viral infections by direct elimination of infected cells and secretion of a number of soluble factors. In HIV-1 infection, persistent HIV-1 specific IFN-γ+ CD8+ T cell responses are detected in the setting of disease progression, consistent with functional impairment in vivo. Recent data suggest that impaired maturation, as defined by the lineage markers CD45RA and CCR7, may contribute to a lack of immune control by these responses. Methodology/Principal Findings: We investigated the maturation phenotype of epitope-specific CD8+ T cell responses directed against HIV-1 in 42 chronically infected, untreated individuals, 22 of whom were “Controllers” (median 1140 RNA copies/ml plasma, range less than 50 to 2520), and 20 “progressors” of whom had advanced disease and high viral loads (median 135,500 RNA copies/ml plasma, range 12100 to greater than 750000). Evaluation of a mean of 5 epitopes per person revealed that terminally differentiated CD8+ T cells directed against HIV-1 are more often seen in HIV-1 Controllers (16/22; 73%) compared to HIV-1 progressors (7/20; 35%)(p = 0.015), but the maturation state of epitope-specific responses within a given individual was quite variable. Maturation phenotype was independent of the HLA restriction or the specificity of a given CD8+ T cell response and individual epitopes associated with slow disease progression were not more likely to be terminally differentiated. Conclusions/Significance: These data indicate that although full maturation of epitope-specific CD8+ T cell responses is associated with viral control, the maturation status of HIV-1 specific CD8+ T cell responses within a given individual are quite heterogeneous, suggesting epitope-specific influences on CD8+ T cell function

HLA Alleles Associated with Delayed Progression to AIDS Contribute Strongly to the Initial CD8+ T Cell Response against HIV-1

Background: Very little is known about the immunodominance patterns of HIV-1-specific T cell responses during primary HIV-1 infection and the reasons for human lymphocyte antigen (HLA) modulation of disease progression. Methods and Findings: In a cohort of 104 individuals with primary HIV-1 infection, we demonstrate that a subset of CD8+ T cell epitopes within HIV-1 are consistently targeted early after infection, while other epitopes subsequently targeted through the same HLA class I alleles are rarely recognized. Certain HLA alleles consistently contributed more than others to the total virus-specific CD8+ T cell response during primary infection, and also reduced the absolute magnitude of responses restricted by other alleles if coexpressed in the same individual, consistent with immunodomination. Furthermore, individual HLA class I alleles that have been associated with slower HIV-1 disease progression contributed strongly to the total HIV-1-specific CD8+ T cell response during primary infection. Conclusions: These data demonstrate consistent immunodominance patterns of HIV-1-specific CD8+ T cell responses during primary infection and provide a mechanistic explanation for the protective effect of specific HLA class I alleles on HIV-1 disease progression

Effects of thymic selection of the T cell repertoire on HLA-class I associated control of HIV infection

Without therapy, most people infected with human immunodeficiency virus (HIV) ultimately progress to AIDS. Rare individuals (‘elite controllers’) maintain very low levels of HIV RNA without therapy, thereby making disease progression and transmission unlikely. Certain HLA class I alleles are markedly enriched in elite controllers, with the highest association observed for HLA-B57 (ref. 1). Because HLA molecules present viral peptides that activate CD8+ T cells, an immune-mediated mechanism is probably responsible for superior control of HIV. Here we describe how the peptide-binding characteristics of HLA-B57 molecules affect thymic development such that, compared to other HLA-restricted T cells, a larger fraction of the naive repertoire of B57-restricted clones recognizes a viral epitope, and these T cells are more cross-reactive to mutants of targeted epitopes. Our calculations predict that such a T-cell repertoire imposes strong immune pressure on immunodominant HIV epitopes and emergent mutants, thereby promoting efficient control of the virus. Supporting these predictions, in a large cohort of HLA-typed individuals, our experiments show that the relative ability of HLA-B alleles to control HIV correlates with their peptide-binding characteristics that affect thymic development. Our results provide a conceptual framework that unifies diverse empirical observations, and have implications for vaccination strategies.Mark and Lisa Schwartz FoundationNational Institutes of Health (U.S.) (Director’s Pioneer award)Philip T. and Susan M. Ragon FoundationJane Coffin Childs Memorial Fund for Medical ResearchBill & Melinda Gates FoundationNational Institute of Allergy and Infectious Diseases (U.S.)National Institutes of Health (U.S.) (contract no. HHSN261200800001E)National Institutes of Health (U.S.). Intramural Research ProgramNational Cancer Institute (U.S.)Center for Cancer Research (National Cancer Institute (U.S.)

Changes in Natural Killer Cell Activation and Function during Primary HIV-1 Infection

Background: Recent reports suggest that Natural Killer (NK) cells may modulate pathogenesis of primary HIV-1 infection. However, HIV dysregulates NK-cell responses. We dissected this bi-directional relationship to understand how HIV impacts NK-cell responses during primary HIV-1 infection. Methodology/Principal Findings: Paired samples from 41 high-risk, initially HIV-uninfected CAPRISA004 participants were analysed prior to HIV acquisition, and during viraemic primary HIV-1 infection. At the time of sampling post-infection five women were seronegative, 11 women were serodiscordant, and 25 women were seropositive by HIV-1 rapid immunoassay. Flow cytometry was used to measure NK and T-cell activation, NK-cell receptor expression, cytotoxic and cytokine-secretory functions, and trafficking marker expression (CCR7, a4b7). Non-parametric statistical tests were used. Both NK cells and Tcells were significantly activated following HIV acquisition (p = 0.03 and p,0.0001, respectively), but correlation between NK-cell and T-cell activation was uncoupled following infection (pre-infection r = 0.68;p,0.0001; post-infection, during primary infection r = 0.074;p = 0.09). Nonetheless, during primary infection NK-cell and T-cell activation correlated with HIV viral load (r = 0.32’p = 0.04 and r = 0.35;p = 0.02, respectively). The frequency of Killer Immunoglobulin-like Receptorexpressing (KIRpos) NK cells increased following HIV acquisition (p = 0.006), and KIRpos NK cells were less activated than KIRneg NK cells amongst individuals sampled while seronegative or serodiscordant (p = 0.001;p,0.0001 respectively). During HIV-1 infection, cytotoxic NK cell responses evaluated after IL-2 stimulation alone, or after co-culture with 721 cells, were impaired (p = 0.006 and p = 0.002, respectively). However, NK-cell IFN-y secretory function was not significantly altered. The frequency of CCR7+ NK cells was elevated during primary infection, particularly at early time-points (p,0.0001). Conclusions/Significance: Analyses of immune cells before and after HIV infection revealed an increase in both NK-cell activation and KIR expression, but reduced cytotoxicity during acute infection. The increase in frequency of NK cells able to traffic to lymph nodes following HIV infection suggests that these cells may play a role in events in secondary lymphoid tissue

P04-15. Prevalence of Broadly Neutralizing Antibody Responses During Acute/Early HIV Infection

Background: Determining how cross-reactive neutralizing antibody (NAb) responses develop during natural HIV-1 infection may provide key information to understand the role they play in controlling the infection and in disease progression. Here we investigated the frequency and breadth of broadly NAb responses during acute and early infection in a well controlled cohort, and attempted to characterize the factors associated with the development of such responses. Methods: The plasma of 38 clade B acutely-infected, antiretroviral-naive subjects from two cohorts was screened for breadth of neutralization against a panel of heterologous isolates in an Env pseudovirus neutralization assay. Clade A, B and C variants were chosen from reference panels of viruses, created to evaluate the NAb responses elicited during infection or immunization. Results: Our preliminary screening strategy demonstrated that broadly neutralizing antibodies can be detected in a third of the infected subjects. Breadth of neutralization can develop as early as one year during natural HIV infection, however the majority of breadth was observed at over two years post infection. Conclusion: Cross-reactive NAbs are developed more frequently during early infection than previously thought. The consequences of this 'early' development of cross-reactive NAbs on plasma viremia and disease progression are under investigation. The work described was supported by National Institute of Health grant number R01 AI047708-11

Natural Killer Cell Education Is Associated With a Distinct Glycolytic Profile

NK cells expressing self-inhibitory receptors display increased functionality compared to NK cells lacking those receptors. The acquisition of functional competence in these particular NK-cell subsets is termed education. Little is known about the underlying mechanisms that lead to the functional differences between educated and uneducated NK cells. An increasing number of studies suggest that cellular metabolism is a determinant of immune cell functions. Thus, alterations in cellular metabolic pathways may play a role in the process of NK-cell education. Here, we compared the glycolytic profile of educated and uneducated primary human NK cells. KIR-educated NK cells showed significantly increased expression levels of the glucose transporter Glut1 in comparison to NKG2A-educated or uneducated NK cells with and without exposure to target cells. Subsequently, the metabolic profile of NK-cell subsets was determined using a Seahorse XF Analyzer. Educated NK cells displayed significantly higher rates of cellular glycolysis than uneducated NK cells even in a resting state. Our results indicate that educated and uneducated NK cells reside in different metabolic states prior to activation. These differences in the ability to utilize glucose may represent an underlying mechanism for the superior functionality of educated NK cells expressing self-inhibitory receptors