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 CD56neg/CD16pos (CD56neg) 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. In this regard, the markedly impaired expression/secretion and function of NKp30 and TNF-related apoptosis-inducing ligand, particularly among the CD56neg NK cell subset, largely accounts for the highly defective NK cell–mediated lysis of autologous iDCs. Moreover, mDCs generated from HIV-1 viremic but not aviremic patients are substantially impaired in their ability to secrete interleukin (IL)-10 and -12 and to prime the proliferation of neighboring autologous NK cells, which, in turn, fail to secrete adequate amounts of interferon-γ

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. We demonstrate that a striking decrease in the surface expression of sialic acid–binding immunoglobulin-like lectin 7 (Siglec-7) represents the earliest marker of the aberrant NK-cell dysregulation, which precedes the down-modulation of CD56 mostly occurring in patients with chronic HIV-1 viremia. The combined detection of Siglec-7 and CD56 allows the identification of 2 new pathologic NK-cell subsets expanded preferentially in early (Siglec-7−/CD56+) or chronic (Siglec-7−/CD56−) stages of HIV-1 infection. Remarkably, these phenotypic abnormalities were directly associated with progressive and distinct impairments of NK-cell functions. The aforementioned NK-cell aberrancies could be observed only in the presence of high levels of viral replication and not in patients with low or undetectable HIV-1 viremia, such as long-term nonprogressors or patients having undergone antiretroviral therapy. High frequencies of Siglec-7−/CD56+ and Siglec-7−/CD56− pathologic NK cells reflect the immune and clinical status of HIV-1 infection and can also track the effectiveness of therapy

Governing protracted displacement: an analysis across global, regional and domestic contexts

This working paper explores the governance of protracted displacement across global, regional and domestic levels in the context of the project “Transnational Figurations of Displacement” (TRAFIG). The multiple contemporary crises that have led to forced displacement show not only the limits of a tight definition of ‘refugee’, but also highlight the gaps in international protection frameworks. A significant number of those forcibly displaced are in protracted displacement situations. This paper is an effort to make sense of the legislative and policy frameworks of protection that apply globally, regionally and domestically, and the way in which these frameworks facilitate or hinder solutions for people in protracted displacement. We evaluate how these frameworks contribute (directly or indirectly) to resolving or creating protracted displacement, assess how they contribute to relevant policy developments and identify engagement trends and (unintended) effects. Along the way, we also draw comparative insights across different global, regional and domestic levels, including eight different countries that host large groups of displaced people and are the focus of the TRAFIG project: Greece, Germany and Italy in Europe; Ethiopia, the Democratic Republic of Congo (DRC) and Tanzania in Africa; and Jordan and Pakistan in Asia. We explore some selected gaps in the current systems of governance of displacement, while concentrating on three key perspectives: governing protection, exercising rights and accessing services, and mobility and transnational dimensions of displacement. We conclude with ten key messages regarding the shortcomings of the current governance system of displacement. They highlight the need for stronger stakeholder collaboration, integration of global and local policies, enhanced focus on IDPs, investment in progressive regional policies, redesign of EU policies to avoid promotion of protracted displacement, greater ownership of processes and resources, de-politicisation of displacement policies, alignment of durable solutions with development-oriented interventions, realisation of the development potential of refugee integration. They also focus on mobility and translocal connectivity as a fourth durable solution to protracted displacement

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. Here, we stimulate primary CD4+ T cells, purified ex vivo from HIV-1-infected viremic patients, with PHA and rIL2 (with or without rIL-7). This experimental procedure allows for the significant expansion and isolation of endogenously infected CD4+ T cell blasts detected by intracellular staining of p24 HIV-1 core antigen. We show that, subsequent to the selective down-modulation of MHC class-I (MHC-I) molecules, HIV-1-infected p24 pos blasts become partially susceptible to lysis by rIL-2-activated NK cells, while uninfected p24neg blasts are spared from killing. This NK cell-mediated killing occurs mainly through the NKG2D activation pathway. However, the degree of NK cell cytolytic activity against autologous, endogenously HIV-1-infected CD4+ T cell blasts that down-modulate HLA-A and -B alleles and against heterologous MHC-Ineg cell lines is particularly low. This phenomenon is associated with the defective surface expression and engagement of natural cytotoxicity receptors (NCRs) and with the high frequency of the anergic CD56neg/CD16pos subsets of highly dysfunctional NK cells from HIV-1-infected viremic patients. Collectively, our data demonstrate that the chronic viral replication of HIV-1 in infected individuals results in several phenotypic and functional aberrancies that interfere with the NK cell-mediated killing of autologous p24pos blasts derived from primary T cells

Long-term proactive management of psoriasis with calcipotriol and betamethasone dipropionate foam: an Italian consensus through a combined nominal group technique and Delphi approach

none85Background: Although long-term management of psoriasis is paramount, this approach is challenging in clinical practice. In the recent PSO-LONG trial, a fixed-dose combination of betamethasone dipropionate (BD) and calcipotriol (Cal) foam applied twice a week on non-consecutive days for 52 weeks (proactive treatment) reduced the risk of relapse. However, the role of Cal/BD foam in the long-term management of psoriasis needs further clarifications. The ProActive Management (PAM) program, a nationwide Italian project, aims at reaching a consensus on the role of proactive management of psoriasis. Methods: A steering committee generated some statements through the nominal group technique (NGT). The statements were voted by an expert panel in an adapted Delphi voting process. Results: Eighteen statements were proposed, and the majority of them (14/18) reached a consensus during the Delphi voting. The need to provide long-term proactive topical treatment to reduce the risk of relapse for the treatment of challenging diseases sites or in patients where phototherapy or systemic therapies are contraindicated/ineffective was widely recognized. A consensus was reached about the possibility to associate the proactive treatment with systemic and biological therapies, without the need for dose intensification, thus favoring a prolonged remission. Moreover, the proactive treatment was recognized as more effective than weekend therapy in increasing time free from relapses. Approaches to improve adherence, on the other hand, need further investigation. Conclusions: The inclusion in guidelines of a proactive strategy among the effective treatment options will be a fundamental step in the evolution of a mild-moderate psoriasis therapeutic approach.noneDe Simone, Clara; Dapavo, Paolo; Malagoli, Piergiorgio; Martella, Alessandro; Campanati, Anna; Campione, Elena; Errichetti, Enzo; Franchi, Chiara; Gambardella, Alessio; Megna, Matteo; Osti, Federica; Ribero, Simone; Zagni, Giovanni; Calzavara-Pinton, Piergiacomo; Fabbrocini, Gabriella; Amoruso, Giuseppe Fabrizio; Baglieri, Francesco; Biamonte, Anna Silvia; Bianchelli, Tommaso; Bigi, Laura; Bortoli, Jarno; Brunetti, Bruno; Buligan, Cinzia; Cagni, Elisabetta; Calderoni, Ombretta; Calzavara-Pinton, Piergiacomo; Campanati, Anna; Caputo, Alighiero; Carrera, Carlo Giovanni; Carugno, Andrea; Chersi, Karin; Cicchelli, Stefano; De Natale, Flora; De Simone, Clara; Dapavo, Paolo; Di Maria, Domenico; Errichetti, Enzo; Fabbrocini, Gabriella; Ferrari, Angelo Salvatore; Fogli, Emanuela; Forconi, Riccardo; Franchi, Chiara; Galeazzi, Augusto; Gambardella, Alessio; Giovannini, Andrea; Giura, Maria Teresa; Iuculano, Massimo; Lazzaretti, Giuseppe; Leporati, Claudia; Magnanini, Massimiliano; Malagoli, Piergiorgio; Marconi, Barbara; Martella, Alessandro; Maruccia, Adriana; Megna, Matteo; Miglietta, Roberta; Minuti, Anna; Mocci, Luigi; Modica, Sonia; Narcisi, Alessandra; Odorici, Giulia; Osti, Federica; Pazzaglia, Massimiliano; Peila, Rossana; Pertusi, Ginevra; Pezza, Michele; Pezzullo, Elio; Puccia, Nunzio; Raulo, Umberto; Ribero, Simone; Rossi, Mariateresa; Rusignuolo, Sergio; Sapienza, Giada; Savarese, Catello; Scalisi, Mariaelena; Strippoli, Davide; Stroppiana, Elena; Tiberio, Rossana; Trischitta, Antonino; Tucci, Maria Giovanna; Vaira, Fabrizio; Verrone, Anna; Villa, Lucia; Zagni, Fabio; Zoccali, AndreaDe Simone, Clara; Dapavo, Paolo; Malagoli, Piergiorgio; Martella, Alessandro; Campanati, Anna; Campione, Elena; Errichetti, Enzo; Franchi, Chiara; Gambardella, Alessio; Megna, Matteo; Osti, Federica; Ribero, Simone; Zagni, Giovanni; Calzavara-Pinton, Piergiacomo; Fabbrocini, Gabriella; Amoruso, Giuseppe Fabrizio; Baglieri, Francesco; Biamonte, Anna Silvia; Bianchelli, Tommaso; Bigi, Laura; Bortoli, Jarno; Brunetti, Bruno; Buligan, Cinzia; Cagni, Elisabetta; Calderoni, Ombretta; Calzavara-Pinton, Piergiacomo; Campanati, Anna; Caputo, Alighiero; Carrera, Carlo Giovanni; Carugno, Andrea; Chersi, Karin; Cicchelli, Stefano; De Natale, Flora; De Simone, Clara; Dapavo, Paolo; Di Maria, Domenico; Errichetti, Enzo; Fabbrocini, Gabriella; Ferrari, Angelo Salvatore; Fogli, Emanuela; Forconi, Riccardo; Franchi, Chiara; Galeazzi, Augusto; Gambardella, Alessio; Giovannini, Andrea; Giura, Maria Teresa; Iuculano, Massimo; Lazzaretti, Giuseppe; Leporati, Claudia; Magnanini, Massimiliano; Malagoli, Piergiorgio; Marconi, Barbara; Martella, Alessandro; Maruccia, Adriana; Megna, Matteo; Miglietta, Roberta; Minuti, Anna; Mocci, Luigi; Modica, Sonia; Narcisi, Alessandra; Odorici, Giulia; Osti, Federica; Pazzaglia, Massimiliano; Peila, Rossana; Pertusi, Ginevra; Pezza, Michele; Pezzullo, Elio; Puccia, Nunzio; Raulo, Umberto; Ribero, Simone; Rossi, Mariateresa; Rusignuolo, Sergio; Sapienza, Giada; Savarese, Catello; Scalisi, Mariaelena; Strippoli, Davide; Stroppiana, Elena; Tiberio, Rossana; Trischitta, Antonino; Tucci, Maria Giovanna; Vaira, Fabrizio; Verrone, Anna; Villa, Lucia; Zagni, Fabio; Zoccali, Andre