PDL-1 upregulation on monocytes and T cells by HIV via type I interferon : restricted expression of type I interferon receptor by CCR5-expressing leukocytes

The programmed death (PD)-1 interacts with its ligand (PDL-1) delivering a negative signal to T cells. During human immunodeficiency virus (HIV)-1 infection PD-1 and PDL-1 expressions are increased. Here we show that monocytes and CCR5(+) T cells of HIV-uninfected donors upregulated PDL-1 upon in vitro exposure to HIV. HIV-induced PDL-1 required interferon (IFN)-alpha, but not IFN-gamma, production. Inhibition of endocytosis, required for HIV-induced IFN-alpha production, prevented PDL-1 upregulation. IFN-alpha-inducing Toll-like receptor (TLR) agonists increased PDL-1 on monocytes and CCR5(+) T cells. CD80 and CD86 were also increased on monocytes and CCR5(+) T cells after HIV exposure, but only CD80 was IFN-alpha-dependent. IFN-alpha-receptor subunit 2 (IFNAR2), was expressed only by CCR5(+) T cells and monocytes, explaining why these leukocytes responded to HIV-induced IFN-alpha. Finally, T cell proliferation was improved by PDL-1 blockade in HIV-treated PBMC. In the setting of HIV infection, IFN-alpha may negatively affect T cell responses by inducing PDL-1

Antigen-stimulated apoptotic T-cell death in HIV infection is selective for CD4+ T cells, modulated by cytokines and effected by lymphotoxin

Objective: To characterize the mechanism of in vitro antigen-induced apoptotic T-cell death in the peripheral blood mononuclear cells (PBMC) of HIV-1-infected individuals. Design and methods: PBMC from HIV-1-infected and uninfected individuals were unstimulated or stimulated with HIV-1 envelope synthetic peptides (Env) or influenza A virus to determine the extent of antigen-stimulated apoptotic T-cell death, whether this death was limited to the CD4+ subset, and the effects of cytokines on T-cell death. Death was assessed by apoptotic nuclear morphology after 7 days of culture by fluorescence microscopy using a DNA-specific dye. Transwell cultures and supernatant transfers were utilized to test whether a soluble factor produced by HIV-positive PBMC induced death of HIV-negative T cells. Exogenous cytokines [interleukin (IL)-12, interferon (IFN)-\u3b3, IL-4 and IL-10], as well as antibodies against endogenously produced cytokines (IL-4, IL-10, IL-12, and lymphotoxin) were tested for their ability to modulate death. Results: Antigenic stimulation induced death in PBMC from HIV-positive donors, but not in PBMC from HIV-negative donors. Antigen-stimulated death was seen in CD4+ but not CD8+ T-cell subset from the HIV-positive patients. Apoptotic death was blocked by IL-12, IFN-\u3b3, anti-IL-4, anti-IL-10, and anti-lymphotoxin, but not by anti-IL-12. Transwell and supernatant transfer experiments indicated that antigen stimulated HIV-positive PBMC produced a factor that killed T-cell blasts. The factor was inhibited by anti-lymphotoxin, but not by anti-IL-10. Conclusions: Stimulation of HIV-positive PBMC with CD4-dependent antigens results in selective death of CD4+ T cells that is modulated by cytokines. Our results suggest that apoptotic death is not limited to HIV-infected or HIV-specific T cells, but occurs in bystander cells. Lymphotoxin is a mediator of antigen-stimulated T-cell death in this in vitro model

A Sketching Tool for Designing Anyuser, Anyplatform, Anywhere User Interfaces

Abstract. Sketching activities are widely adopted during early design phases of user interface development to convey informal specifications of the interface presentation and dialog. Designers or even end users can sketch some or all of the future interface they want. With the ever increasing availability of different computing platforms, a need arises to continuously support sketching across these platforms with their various programming languages, interface development environments and operating systems. To address needs along these dimensions, which pose new challenges to user interface sketching tools, SketchiXML is a multi-platform multi-agent interactive application that enable designers and end users to sketch user interfaces with different levels of details and support for different contexts of use. The results of the sketching are then analyzed to produce interface specifications independently of any context, including user and platform. These specifications are exploited to progressively produce one or several interfaces, for one or many users, platforms, and environments.

Mediastinal histoplasmosis: report of the first two Brazilian cases of mediastinal granuloma Histoplasmose mediastinal: relato dos dois primeiros casos brasileiros de granuloma mediastinal

This report documents the first two Brazilian cases of mediastinal granuloma due to histoplasmosis, presenting selected aspects on the diagnosis. Tissue samples revealing histoplasmosis were obtained from each of the patients by mediastinoscopy and thoracotomy. In the second patient, a subcarinal calcified mass eroded into the bronchial tree, leading to secondary bilateral aspiration pneumonitis one week after thoracotomy. Although rare, histoplasmosis should be included in the differential diagnosis of mediastinal granuloma, specially if there are calcifications greater than 10 mm in dimension.<br>São relatados os dois primeiros casos de granuloma mediastinal por histoplasmose no Brasil, apresentando aspectos selecionados sobre dignóstico. O diagnóstico tecidual de histoplasmose foi obtido por mediastinoscopia e toracotomia, respectivamente. Em um paciente a massa calcificada subcarinal erodiu na árvore brônquica com pneumonite de aspiração bilateral uma semana após a toracotomia. Embora rara, histoplasmose deve ser incluída no diagnóstico diferencial de granuloma mediastinal especialmente com calcificação maior do que 10 mm de diâmetro