For timing of HAART is less more? CD4+/CD8+ ratio and CD4+ percentage as surrogate markers for more complex immunological features.

There is disagreement on the optimal timing of HAART initiation based on absolute CD4+ T-cell count (CD4+ count). We investigated if na�ve patients with CD4+ T-cell percentage (%CD4+) <29% or CD4+/CD8+ ratio <1 display signs of immune deterioration notwithstanding CD4+ count ?500 cells/?l. We found that these patients show B-cell aberrations and an impaired control of Torque Teno Virus replication.

Profile of toll-like receptors on peripheral blood cells in relation to acute graft-versus-host disease after allogeneic stem cell transplantation.

Toll-like receptors (TLRs) play a key role in the cross-talk between the innate and adaptive immune systems. Previous studies investigating associations between certain TLRs and acute graft-versus-host disease (aGVHD) have reported contrasting results, and no studies relating aGVHD to the expression and function of all human TLRs together have been published to date. We prospectively evaluated the expression of 9 TLRs on T lymphocytes and monocytes by flow cytometry in relation to aGVHD in 34 patients.

Emergence of exhausted B cells in asymptomatic HIV-1-infected patients naïve for HAART is related to reduced immune surveillance.

Alterations of B cell subpopulations have been described up to date as characterizing advanced stage of HIV-1 infection. However, whether such defects are relevant in subjects with a preserved number of CD4⁺ T cells (>350 cells/μL) is unclear. In a cross-sectional study, we investigated if signs of B cells exhaustion and impaired viral immune surveillance are present in a cohort of 43 asymptomatic HIV-1-infected patients with preserved CD4⁺ T cell counts (>350 cells/μL) and highly active antiretroviral therapy (HAART) untreated.

Engagement of NKp30 on Vδ1 T cells induces the production of CCL3, CCL4, and CCL5 and suppresses HIV-1 replication.

Natural cytotoxicity receptors (NCRs) were originally identified as specific natural killer cell activating receptors that, on binding to their endogenous ligands, trigger the killing of tumor cell targets. We recently described the differentiation of a novel subset of NCR(+) Vδ1 T cells characterized by a remarkably high cytolytic potential against cancer cells. Here we demonstrate that the engagement of NKp30, one of the NCRs expressed de novo on Vδ1 T cells after stimulation, triggers the production of high levels of CCL3/MIP-1α, CCL4/ MIP-1β, and CCL5/RANTES but not of CXCL12/SDF-1.

Differentiation of human peripheral blood Vδ1+ T cells expressing the natural cytotoxicity receptor NKp30 for recognition of lymphoid leukemia cells.

The success of cancer immunotherapy depends on productive tumor cell recognition by killer lymphocytes. γδ T cells are a population of innate-like lymphocytes endowed with strong, MHC-unrestricted cytotoxicity against tumor cells. This notwithstanding, we recently showed that a large proportion of human hematologic tumors is resistant to γδ peripheral blood lymphocytes (PBLs) activated with specific agonists to the highly prevalent Vγ9Vδ2 TCR.

Dendritic cells/natural killer cross-talk: a novel target for human immunodeficiency virus type-1 protease inhibitors.

Background: HIV-1 Protease Inhibitors, namely PIs, originally designed to inhibit HIV-1 aspartic protease, can modulate the immune response by mechanisms largely unknown, and independent from their activity on viral replication. Here, we analyzed the ability of PIs to interfere with differentiation program of monocytes toward dendritic cell (DCs) lineage, a key process in the inflammatory response.

Methodology/principal Findings: Monocytes from healthy donors were isolated and induced to differentiate in vitro in the presence or absence of saquinavir, ritonavir, nelfinavir, indinavir or amprenavir (sqv, rtv, nlfv, idv, apv, respectively).

CD8+ NK cells are predominant in chimpanzees, characterized by high NCR expression and cytokine production, and preserved in chronic HIV-1 infection.

HIV-1 infection in humans results in an early and progressive NK cell dysfunction and an accumulation of an "anergic" CD56- CD16+ NK subset, which is characterised by low natural cytotoxicity receptor expression and low cytokine producing capacity. In contrast to humans, chimpanzee NK cells do not display a distinguishable CD56(bright) and CD56(dim) subset but, as shown here, could be subdivided into functionally different CD8+ and CD8- subsets. The CD8+ NK cells expressed significantly higher levels of triggering receptors including NKp46 and, upon in vitro activation, produced more IFN-gamma, TNF-alpha and CD107 than their CD8- counterparts.

Chronic HIV-1 viremia reverses NKG2A/NKG2C ratio on natural killer cells in patients with human cytomegalovirus co-infection.

Background: The HIV-1-induced expansion of highly dysfunctional natural killer (NK) cell subsets represents a strategy to evade NK cell antiviral functions. In this context, the loss of NKG2A NK cells in chronic viremic HIV-1-infected individuals has also been associated with a dramatic expansion of NKG2C NK cells. The viral trigger associated with high frequencies of NK cell subsets expressing NKG2C is still being debated.

The decreased expression of Siglec-7 represents an early marker of dysfunctional natural killer-cell subsets associated with high levels of HIV-1 viremia.

HIV-1 has developed several strategies to evade natural killer (NK)-cell antiviral functions. One of these mechanisms is the HIV-1-induced expansion of highly dysfunctional NK-cell subsets. Here, we analyze a large cohort of HIV-1-infected patients in early or chronic phases of infection, both cross-sectionally and longitudinally.

Lysis of endogenously infected CD4+ T cell blasts by rIL-2 activated autologous natural killer cells from HIV-infected viremic individuals.

Understanding the cellular mechanisms that ensure an appropriate innate immune response against viral pathogens is an important challenge of biomedical research. In vitro studies have shown that natural killer (NK) cells purified from healthy donors can kill heterologous cell lines or autologous CD4+ T cell blasts exogenously infected with several strains of HIV-1. However, it is not known whether the deleterious effects of high HIV-1 viremia interferes with the NK cell-mediated cytolysis of autologous, endogenously HIV-1-infected CD4+ T cells.

HIV modulates the expression of ligands important in triggering natural killer cell cytotoxic responses on infected primary T-cell blasts.

The ability of natural killer (NK) cells to kill virus-infected cells depends on the presence of ligands for activation receptors on the target cells. We found the presence of few, if any, NKp30 and NK46 ligands on T cell blasts infected with HIV, although NKp44 ligands were found on infected cells. HIV does induce the NKG2D ligands ULBP-1, -2, and -3.

Increased natural cytotoxicity receptor expression and relevant IL-10 production in NK cells from chronically infected viremic HCV patients.

Hepatitis C virus (HCV) readily establishes high-level lifelong persistent infection in the majority of immunocompetent adults with failure of HCV-specific CD8+ CTL to clear viral replication. Virus-induced conditioning of innate immune responses is a possible mechanism that may contribute to the impairment of virus-specific CD8+ CTL responses. Here, we analyzed whether triggering of NK cell receptor expression and function is affected during chronic viremic HCV infection.

Differential NKp30 inducibility in chimpanzee NK cells and conserved NK cell phenotype and function in long-term HIV-1-infected animals.

HIV-1 infection in chimpanzees, the closest human relative, rarely leads to disease progression. NK cells contribute to the shaping of adaptive immune responses in humans and show perturbed phenotype and function during HIV-1 infection. In this study, we provide full phenotypic, molecular, and functional characterization for triggering molecules (NKp46, NKp30 NKp80, and NKG2D) on Pan troglodytes NK cells.

Characterization of the defective interaction between a subset of natural killer cells and dendritic cells in HIV-1 infection.

In this study, we demonstrate that the in vitro interactions between a CD56(neg)/CD16(pos) (CD56(neg)) subset of natural killer (NK) cells and autologous dendritic cells (DCs) from HIV-1-infected viremic but not aviremic individuals are markedly impaired and likely interfere with the development of an effective immune response. Among the defective interactions are abnormalities in the process of reciprocal NK-DC activation and maturation as well as a defect in the NK cell-mediated editing or elimination of immature DCs (iDCs). Notably, the lysis of mature DCs (mDCs) by autologous NK cells was highly impaired even after the complete masking of major histocompatibility complex I molecules, suggesting that the defective elimination of autologous iDCs is at the level of activating NK cell receptors.

Membrane-bound and soluble IL-15/IL-15Ralpha complexes display differential signaling and functions on human hematopoietic progenitors.

Membrane-bound and soluble interleukin-15 (IL-15)/IL-15 receptor alpha (Ralpha) complexes trigger differential transcription factor activation and functions on human hematopoietic progenitors. Indeed, human spleen myofibroblasts (SMFs) are characterized by a novel mechanism of IL-15 trans-presentation (SMFmb [membrane-bound]-IL-15), based on the association of an endogenous IL-15/IL-15Ralpha complex with the IL-15Rbetagamma c chains. SMFmb-IL-15 (1) induces lineage-specific signaling pathways that differ from those controlled by soluble IL-15 in unprimed and committed normal progenitors; (2) triggers survival and proliferation of leukemic progenitors expressing low-affinity IL-15R (M07Sb cells); (3) causes only an antiapoptotic effect on leukemic cells expressing high-affinity receptors (TF1beta cells).

Molecular and functional characterization of NKG2D, NKp80, and NKG2C triggering NK cell receptors in rhesus and cynomolgus macaques: monitoring of NK cell function during simian HIV infection.

An involvement of innate immunity and of NK cells during the priming of adaptive immune responses has been recently suggested in normal and disease conditions such as HIV infection and acute myelogenous leukemia. The analysis of NK cell-triggering receptor expression has been so far restricted to only NKp46 and NKp30 in Macaca fascicularis. In this study, we extended the molecular and functional characterization to the various NK cell-triggering receptors using PBMC and to the in vitro-derived NK cell populations by cytofluorometry and by cytolytic activity assays.

Significant NK cell activation associated with decreased cytolytic function in peripheral blood of HIV-1-infected patients.

One of the hallmarks of HIV-1 infection is represented by the finding of massive T cell activation in peripheral blood lymphocytes of infected patients. An impairment of NK cell function during HIV-1 infection is also detected, and is associated with decreased expression of natural cytotoxicity receptors (NCR). In this study we tried to determine whether also NK cells are affected by relevant activation and whether this could be associated with decreased NK cell function.

The impaired NK cell cytolytic function in viremic HIV-1 infection is associated with a reduced surface expression of natural cytotoxicity receptors (NKp46, NKp30 and NKp44).

Signals leading to NK cell triggering are primarily mediated by natural cytotoxicity receptors (NCR) upon binding to as-yet-undefined cell surface ligand(s) on normal hematopoietic cells, pathogen-infected cells or tumor cells. In this study we tried to determine whether the decreased NK cell cytolytic function that is observed in HIV-1-infected patients may be related to a decreased expression of NCR. In HIV-1-infected patients, freshly drawn, purified NK cells expressed significantly decreased surface densities of NKp46 and NKp30 NCR.

Differential STAT3, STAT5, and NF-kappaB activation in human hematopoietic progenitors by endogenous interleukin-15: implications in the expression of functional molecules.

Different forms of interleukin-15 (IL-15) have been identified and shown to elicit different transduction pathways whose impact on hematopoiesis is poorly understood. We demonstrated herein that hematopoietic CD34+ cells constitutively produced endogenous secreted IL-15 (ES-IL-15) that activated different transcription factors and controlled the expression of several functional proteins, depending on the progenitor source. Thus, nuclear factor-kappa B (NF-kappa B) was activated in bone marrow (BM) and cord blood (CB) progenitors, whereas signal transducer and activator of transcription 3 (STAT3) and STAT5 activation was restricted to peripheral granulocyte-colony-stimulating factor (G-CSF)-mobilized and BM progenitors, respectively.

Low expression of inhibitory natural killer receptors in CD8 cytotoxic T lymphocytes in long-term non-progressor HIV-1-infected patients.

We investigated whether a different pattern of HLA-specific inhibitory natural killer receptor (iNKR) expression on peripheral blood mononuclear cells (PBMC) of long-term non-progressor (LTNP) patients explained their benign course of HIV-1 infection. The surface expression of p70, p140 and CD94/NKG2A in their CD3+CD8+ PBMC was comparable to that of uninfected donors. The lack of iNKR-mediated functional inhibition of HIV-1-specific cytotoxic T lymphocytes in vitro could provide an additional mechanism for the efficient control of virus spread in LTNP patients.