HIV infection induces a progressive depletion of CD4 T cells. We showed that NKp44L, a cellular ligand for an activating natural killer (NK) receptor, is expressed on CD4 T cells during HIV infection and is correlated with both CD4 cell depletion and increase in viral load. NKp44LCD4 T cells are highly sensitive to the NK lysis activity. In contrast, HIV-infected CD4 T cells are resistant to NK killing, suggesting that HIV-1 developed strategies to avoid detection by the host cell immunity.
To assess whether viral protein can affect NKp44L expression, using Nef-deficient virus as well as a panel of recombinant vaccinia viruses expressing all HIV-1 viral proteins was tested. The involvement of Nef in the downmodulation of NKp44L was determined using defined mutants of Nef. Functional consequences of Nef on NK-cell recognition were evaluated by either 51Cr-release assays and degranulation assays in presence of anti-NKp44L mAb.
We observed that during HIV-1 infection, noninfected CD4 T cells exclusively expressed NKp44L, and demonstrate that Nef mediates NKp44L intracellular retention in HIV-infected cells. This has functional consequences on HIV-infected CD4 T cells recognition by NK cells, causing a decreased susceptibility to NK cytotoxicity. Furthermore, experiments in presence of neutralizing NKp44L mAb revealed that Nef inhibitory effect on NK cytotoxicity mainly depends on the NKp44L pathway.
This novel escape mechanism could explain the resistance of HIV-infected cells to NK lysis and as a result play a key role in maintaining the HIV reservoir by avoiding recognition by NK cells.
"However, the expression of NKG2D-L on activated CD4+ and CD8+ T cells, in response to super-antigens, alloantigens or to a specific antigenic peptides, is variable, depending on the donors, but also on the time-stimulation of T cells and the experimental settings (28). Other and us have also reported this variability of cell-surface expression, for ligands of NCRs and NKG2D in various pathologic situations (22, 45). The expression and function of PVR, a ligand of DNAM-1, another activating NK receptor, was also investigated on T cells in response to super-antigen stimulations (50). "
[Show abstract][Hide abstract] ABSTRACT: Natural killer (NK) cells are an essential component of innate immunity that provides a rapid response to detect stressed, infected, or transformed target cells. This system is controlled by a balance of inhibitory and activating signals transmitted by a myriad of receptors and their specific ligands. Inhibitory receptors mainly recognize self-MHC class-I molecules, whereas activating receptors, such as natural cytotoxic receptors, NKG2D, and DNAM-1, interact with self-proteins, normally not expressed on the cell surface of healthy cells, but up-regulated by cellular stress or infections and are frequently expressed on tumor cells. In these circumstances, regulatory controls ensure that specific ligands are induced mainly in diseased cells and not in normal cells. Each ligand seems to exhibit some distinct specializations providing broad "coverage" for numerous stresses associated with various diseases. Deregulated cell proliferation is a hallmark of these abnormal situations, and may serve as a sentinel for the elimination of the targets by NK cells. The purpose of this review is to discuss recent implications of cell-cycle to create a warning control system that relays various danger signals via specific ligands to the NK receptor system.
Frontiers in Immunology 10/2013; 4:325. DOI:10.3389/fimmu.2013.00325
"Betser-Cohen et al. recently found HLA I proteins coimmunoprecipitate with anti-NKp44 antibodies; reciprocally, NKp44 coimmunoprecipitates with anti-β-2-microglobulin antibodies . Additionally, the Nef protein of HIV prevents surface expression of the activating NKp44 ligand on CD4 infected T cells, which is also consistent with the ability of Nef to retain HLA I intracellularly , . Finally, Human Leukocyte Antigen-B associated Transcript 3 (Bat3), typically found in the nucleus, colocalizes with HLA I on the cell membrane of dendritic cells and tumor cells after nonlethal heat shock where it binds NKp30, activating NK cell effector functions , . "
[Show abstract][Hide abstract] ABSTRACT: NK cell function is closely regulated by numerous inhibitory and activating receptors binding corresponding ligands on the surface of target cells, providing vital first line defenses against infections and cancer. NKp44, originally discovered as an activating NK cell receptor, was recently found to elicit inhibitory effects on NK cell effector function through recognition of cell surface PCNA. Other reports have pointed to potential associations between NKp44 and HLA I molecules, as well as HLA I and Damage Associated Molecular Pattern molecules (DAMPs) on the surface of tumor cells. In this report, we have identified novel interaction between HLA I and PCNA on the surface of human tumor cells by confocal microscopy and immunoprecipitation. In addition to previous reports, we show PCNA on the cell surface where novel association with HLA I does not require the presence of NKp44 expressing NK cells and occurs with endogenous PCNA. The association of HLA I and PCNA forms the inhibitory ligand for NKp44, resulting in inhibition of NK cell cytotoxicity. We further postulate NCR ligands are composed of DAMP molecules localized to the cell surface, colocalizing with HLA I, and potentially heparin sulfate proteoglycans.
PLoS ONE 03/2013; 8(3):e59552. DOI:10.1371/journal.pone.0059552 · 3.23 Impact Factor
"Third, it is critical to understand whether NK cells have immunopathological effects in addition to their putative protective functions in acute and early HIV infection. NK cells may contribute to immunopathological CD4+ T cell destruction, e.g. a role for NKp44-expressing NK cells in mediating lysis of uninfected CD4+ T cells expressing a gp41 peptide-induced NKp44 ligand has been suggested . NK cells may also promote immune activation via either direct or indirect mechanisms, hence enhancing viral replication and spread. "
[Show abstract][Hide abstract] ABSTRACT: This review summarizes recent advances and current gaps in understanding of innate immunity to human immunodeficiency virus (HIV) infection, and identifies key scientific priorities to enable application of this knowledge to the development of novel prevention strategies (vaccines and microbicides). It builds on productive discussion and new data arising out of a workshop on innate immunity against HIV held at the European Commission in Brussels, together with recent observations from the literature.
Increasing evidence suggests that innate responses are key determinants of the outcome of HIV infection, influencing critical events in the earliest stages of infection including the efficiency of mucosal HIV transmission, establishment of initial foci of infection and local virus replication/spread as well as virus dissemination, the ensuing acute burst of viral replication, and the persisting viral load established. They also impact on the subsequent level of ongoing viral replication and rate of disease progression. Modulation of innate immunity thus has the potential to constitute a powerful effector strategy to complement traditional approaches to HIV prophylaxis and therapy. Importantly, there is increasing evidence to suggest that many arms of the innate response play both protective and pathogenic roles in HIV infection. Consequently, understanding the contributions made by components of the host innate response to HIV acquisition/spread versus control is a critical pre-requisite for the employment of innate immunity in vaccine or microbicide design, so that appropriate responses can be targeted for up- or down-modulation. There is also an important need to understand the mechanisms via which innate responses are triggered and mediate their activity, and to define the structure-function relationships of individual innate factors, so that they can be selectively exploited or inhibited. Finally, strategies for achieving modulation of innate functions need to be developed and subjected to rigorous testing to ensure that they achieve the desired level of protection without stimulation of immunopathological effects. Priority areas are identified where there are opportunities to accelerate the translation of recent gains in understanding of innate immunity into the design of improved or novel vaccine and microbicide strategies against HIV infection.
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