Early ART in Acute HIV-1 Infection: Impact on the B-Cell Compartment

HIV-1 infection induces B cell defects, not fully recovered upon antiretroviral therapy (ART). Acute infection and the early start of ART provide unique settings to address the impact of HIV on the B cell compartment. We took advantage of a cohort of 21 seroconverters, grouped according to the presence of severe manifestations likely mediated by antibodies or immune complexes, such as Guillain-Barré syndrome and autoimmune thrombocytopenic purpura, with a follow-up of 8 weeks upon effective ART. We combined B and T cell phenotyping with serum immunoglobulin level measurement and quantification of sj-KRECs and ΔB to estimate bone marrow output and peripheral proliferative history of B cells, respectively. We observed marked B cell disturbances, notably a significant expansion of cells expressing low levels of CD21, in parallel with markers of both impaired bone marrow output and increased peripheral B cell proliferation. This B cell dysregulation is likely to contribute to the severe immune-mediated conditions, as attested by the higher serum IgG and the reduced levels of sj-KRECs with increased ΔB in these individuals as compared to those patients with mild disease. Nevertheless, upon starting ART, the dynamic of B cell recovery was not distinct in the two groups, featuring both persistent alterations by week 8. Overall, we showed for the first time that acute HIV-1 infection is associated with decreased bone marrow B cell output assessed by sj-KRECs. Our study emphasizes the need to intervene in both bone marrow and peripheral responses to facilitate B cell recovery during acute HIV-1 infection.info:eu-repo/semantics/publishedVersio

Human naïve regulatory T-cells feature high steady-state turnover and are maintained by IL-7

Naïve FoxP3-expressing regulatory T-cells (Tregs) are essential to control immune responses via continuous replenishment of the activated-Treg pool with thymus-committed suppressor cells. The mechanisms underlying naïve-Treg maintenance throughout life in face of the age-associated thymic involution remain unclear. We found that in adults thymectomized early in infancy the naïve-Treg pool is remarkably well preserved, in contrast to conventional naïve CD4 T-cells. Naïve-Tregs featured high levels of cycling and pro-survival markers, even in healthy individuals, and contrasted with other circulating naïve/memory CD4 T-cell subsets in terms of their strong γc-cytokine-dependent signaling, particularly in response to IL-7. Accordingly, ex-vivo stimulation of naïve-Tregs with IL-7 induced robust cytokine-dependent signaling, Bcl-2 expression, and phosphatidylinositol 3-kinase (PI3K)-dependent proliferation, whilst preserving naïve phenotype and suppressive capacity. Altogether, our data strongly implicate IL-7 in the thymus-independent long-term survival of functional naïve-Tregs, and highlight the potential of targeting the IL-7 pathway to modulate Tregs in different clinical settings.This work was supported by Fundação para a Ciência e Tecnologia (FCT; POCI2010/IC/83068/2007 to RMMV; PTDC/SAU-MIC/109786/2009 to AES), and Gulbenkian Foundation (96526/2009 to JF; P132532/2013 to AES). SLS, ASA, RBF, ARP, PM and SMF received FCT scholarships

Massive hypereosinophilia and vasculitis associated with major expansion of interleukin-5-producing CD8+ T cells in HIV-1 infection

© 2014 Wolters Kluwer Health | Lippincott Williams & WilkinsThis work was supported by ‘Fundação para a Ciência e a Tecnologia’ (FCT) and by ‘Programa Operacional Ciência e Inovação 2010’ [POCI2010][PIC/IC/82712/2007 to AES], as well as by Fundação Calouste Gulbenkian to AES. RBF and RT received scholarships from FCT

Major Depletion of Plasmacytoid Dendritic Cells in HIV-2 Infection, an Attenuated Form of HIV Disease

Plasmacytoid dendritic cells (pDC) provide an important link between innate and acquired immunity, mediating their action mainly through IFN-α production. pDC suppress HIV-1 replication, but there is increasing evidence suggesting they may also contribute to the increased levels of cell apoptosis and pan-immune activation associated with disease progression. Although having the same clinical spectrum, HIV-2 infection is characterized by a strikingly lower viremia and a much slower rate of CD4 decline and AIDS progression than HIV-1, irrespective of disease stage. We report here a similar marked reduction in circulating pDC levels in untreated HIV-1 and HIV-2 infections in association with CD4 depletion and T cell activation, in spite of the undetectable viremia found in the majority of HIV-2 patients. Moreover, the same overexpression of CD86 and PD-L1 on circulating pDC was found in both infections irrespective of disease stage or viremia status. Our observation that pDC depletion occurs in HIV-2 infected patients with undetectable viremia indicates that mechanisms other than direct viral infection determine the pDC depletion during persistent infections. However, viremia was associated with an impairment of IFN-α production on a per pDC basis upon TLR9 stimulation. These data support the possibility that diminished function in vitro may relate to prior activation by HIV virions in vivo, in agreement with our finding of higher expression levels of the IFN-α inducible gene, MxA, in HIV-1 than in HIV-2 individuals. Importantly, serum IFN-α levels were not elevated in HIV-2 infected individuals. In conclusion, our data in this unique natural model of “attenuated” HIV immunodeficiency contribute to the understanding of pDC biology in HIV/AIDS pathogenesis, showing that in the absence of detectable viremia a major depletion of circulating pDC in association with a relatively preserved IFN-α production does occur

Customer emotions in service failure and recovery encounters

Emotions play a significant role in the workplace, and considerable attention has been given to the study of employee emotions. Customers also play a central function in organizations, but much less is known about customer emotions. This chapter reviews the growing literature on customer emotions in employee–customer interfaces with a focus on service failure and recovery encounters, where emotions are heightened. It highlights emerging themes and key findings, addresses the measurement, modeling, and management of customer emotions, and identifies future research streams. Attention is given to emotional contagion, relationships between affective and cognitive processes, customer anger, customer rage, and individual differences

Enteric mucosa integrity in the presence of a preserved innate interleukin 22 compartment in HIV type 1-treated individuals

© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.Interleukin 22 (IL-22) is emerging as a key cytokine for gut epithelial homeostasis and mucosal repair. Gut disruption is a hallmark of human immunodeficiency virus (HIV) infection. Here, we investigated IL-22 production and gut mucosal integrity in HIV type 1 (HIV-1)-infected individuals receiving long-term antiretroviral therapy (ART).Methods. Biopsy specimens from 37 individuals who underwent colonoscopy primarily for cancer screening and from 17 HIV-1-infected and 20 healthy age-matched controls were assessed.Results. We found significant depletion of sigmoid IL-22-producing CD4+ T cells (T-helper type 22 [Th22] cells) even after prolonged ART, contrasting with the apparently normal compartments of regulatory and interleukin 17 (IL-17)-producing CD4+ T cells, as well as total mucosal CD4+ T cells. Despite the preferential Th22 cell depletion, IL-22 production by innate lymphoid cells (ILCs) was similar to that observed in HIV-1-seronegative subjects, and transcription of genes encoding molecules relevant for IL-22 production (ie, AHR, IL23, IL23R, IL1B, IL6, and TGFB1) was preserved. Remarkably, levels of transcripts of IL-22-target genes (ie, REG3G, DEFB4A, S100A9, MUC1, and MUC13) were unaltered, suggesting an adequate production of antimicrobial peptides and mucins. In agreement, enteric epithelial architecture was fully preserved.Conclusions. Despite the reduced Th22 cell subset, innate IL-22-mediated mechanisms, essential for sigmoid mucosa integrity, were fully operational in long-term-treated HIV-1-infected individuals. Our data highlight IL-22 production by ILCs as an important target for therapies aimed at facilitating human mucosal reconstitution.This work was supported by the Fundação para a Ciência e Tecnologia (FCT) and the Programa Operacional Ciência e Inovação 2010 (PIC/IC/82712/2007 to A. E. S). Scholarships were provided to S. M. F., A. R. P., and R. B. F. by the FCT

PD-1 and its ligand PD-L1 are progressively up-regulated on CD4 and CD8 T-cells in HIV-2 infection irrespective of the presence of viremia.

© 2012 Wolters Kluwer Health | Lippincott Williams & WilkinsObjective: Hyper-immune activation is a main determinant of HIV disease progression, potentially counter-acted by T-cell inhibitory pathways. Here we investigated, for the first time, inhibitory molecules in HIV-2 infection, a naturally occurring attenuated form of HIV disease, associated with reduced viremia and very slow rates of CD4 T-cell decline. Design: Programmed death (PD)-1/PD-L1, an important pathway in limiting immunopathology, and its possible relationship with T-cell immunoglobulin and mucin-domain containing molecule-3 (TIM-3), a recently identified inhibitory molecule, were studied in untreated HIV-2 and HIV-1 cohorts, matched for degree of CD4 T-cell depletion, and noninfected individuals. Methods: Flow cytometric analysis of T-cell expression of PD-1, PD-L1 and TIM-3, combined with markers of cell differentiation, activation, cycling and survival. Statistical analysis was performed using ANOVA, Mann–Whitney/Wilcoxon tests, Spearman's correlations, multiple linear regressions and canonical correlation analysis. Results: T-cell expression of PD-1 and PD-L1 was tightly associated and directly correlated with CD4 T-cell depletion and immune activation in HIV-2 infection. No such correlation was found for PD-L1 expression in HIV-1-positive patients. Central memory and intermediate memory cells, rather than terminally differentiated T-cells, expressed the highest levels of both PD-1 and PD-L1 molecules. Conversely, TIM-3 expression was independent of T-cell differentiation and dissociated from cell cycling, suggesting distinct induction mechanisms. Importantly, in contrast with HIV-1, no significant increases in TIM-3 expression were found in the HIV-2 cohort. Conclusions: Our data suggest that PD-1/PD-L1 molecules, rather than markers of T-cell exhaustion, may act as modulators of T-cell immune activation, contributing to the slower course of HIV-2 infection. These data have implications for the design of antiretroviral therapy-complementary immune-based strategies.The work was supported by grants from ‘Fundação para a Ciência e a Tecnologia’ (FCT) and by ‘Programa Operacional Ciência e Inovação 2010’ (POCI2010), as well as from Fundação Calouste Gulbenkian to A.E.S. R.T., R.B.F., R.S.S., and R.C. received scholarships from FCT