Exosomes as intercellular signalosomes and pharmacological effectors

Record, Michel; Subra, Caroline; Silvente-Poirot, Sandrine; Poirot, Marc

doi:10.1016/j.bcp.2011.02.011

Cited by 476 publications

(355 citation statements)

References 104 publications

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“…In this regard, HIV-1 particles share many properties with cell-derived exosomes (15,(27)(28)(29). Exosomes provide a mechanism of intercellular communication that can allow for the exchange of membrane proteins between cells or the delivery of signaling proteins, mRNA and miRNA (30). Intriguingly, exomsomes can also mediate cross-presentation by entering mDCs, limiting exposure to endosomal acidification (31), and ultimately presenting antigen to T cells in the absence of any fusion events.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 incorporation of host-cell–derived glycosphingolipid GM3 allows for capture by mature dendritic cells

Puryear

Ramirez

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

104

139

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The interaction between HIV and dendritic cells (DCs) is an important early event in HIV-1 pathogenesis that leads to efficient viral dissemination. Here we demonstrate a HIV gp120-independent DC capture mechanism that uses virion-incorporated hostderived gangliosides with terminal α2-3-linked sialic acid linkages. Using exogenously enriched virus and artificial liposome particles, we demonstrate that both α2-3 gangliosides GM1 and GM3 are capable of mediating this interaction when present in the particle at high levels. In the absence of overexpression, GM3 is the primary ligand responsible for this capture mechanism, because siRNA depletion of GM3 but not GM1 from the producer cell and hence virions, resulted in a dramatic decrease in DC capture. Furthermore, HIV-1 capture by DCs was competitively inhibited by targeting virion-associated GM3, but was unchanged by targeting GM1. Finally, virions were derived from monocytoid THP-1 cells that constitutively display low levels of GM1 and GM3, or from THP-1 cells induced to express high surface levels of GM1 and GM3 upon stimulation with the TLR2/1 ligand Pam3CSK4. Compared with untreated THP-1 cells, virus produced from Pam3CSK4-stimulated THP-1 cells incorporated higher levels of GM3, but not GM1, and showed enhanced DC capture and trans-infection. Our results identify a unique HIV-1 DC attachment mechanism that is dependent on a host-cell-derived ligand, GM3, and is a unique example of pathogen mimicry of host-cell recognition pathways that drive virus capture and dissemination in vivo.

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Section: Discussionmentioning

confidence: 99%

HIV-1 incorporation of host-cell–derived glycosphingolipid GM3 allows for capture by mature dendritic cells

Puryear

Ramirez

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

104

139

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“…5,6 Their vesicular content, including nucleic acids, cytokines, enzymes and soluble factors, reflects the cytoplasmic content of the mother cell. 7 Exosomes are present in all body fluids, and they are secreted by cells maintained in culture. 8 While all cells can produce exosomes, tumor cells, including glioma cells, secrete large quantities of exosomes and, consequently, exosomal fractions obtained from plasma of cancer patients are considerably larger than those obtained from normal donor plasma.…”

Section: Introductionmentioning

confidence: 99%

Exosomes isolated from plasma of glioma patients enrolled in a vaccination trial reflect antitumor immune activity and might predict survival

et al. 2015

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Exosomes in plasma of glioma patients hold promise as biomarkers of prognosis. We aimed to determine whether changes in total exosomal protein and mRNA expression levels could serve as surrogate markers of immunological and clinical responses in glioma patients receiving antitumor vaccines. Exosomes were isolated from pre/post-vaccine plasma specimens in 20/22 patients enrolled in a phase I/II trial with the antitumor vaccine. Exosomal protein content was analyzed and mRNA expression levels for 24 genes were simultaneously assessed by qRT-PCR. Pre-to postvaccination changes in exosomal protein and DCt values were correlated with immunological and clinical responses and survival using Spearman rank statistics and hazard ratios (HR). Exosomal protein levels positively correlated (p < 0.0043) with the WHO tumor grade at diagnosis. Protein levels were lower in post-vs. pre-vaccination exosome fractions. Post-therapy increases in tumor size were associated with elevations in exosome proteins in glioblastoma but not always in anaplastic astrocytoma (AA). Only exosomal DCt values for IL-8, TIMP-1, TGF-b and ZAP70 were significant (p < 0.04 to p < 0.001). The DCt for IL-8 and TGF-b mRNA positively correlated with post-vaccine immunologic responses to glioma antigens, while DCt for TIMP-1 mRNA was negatively correlated to DCt for IL-8 and TGF-b. Only DCt for IL-8 weakly correlated with OS and time to progression (TTP). In post-vaccine exosomes of the longest surviving patient with AA, mRNA for PD-1 was persistently elevated. Protein and mRNA expression levels for immune-related genes in plasma exosomes were useful in evaluating glioma patients' response to vaccination therapy.

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“…Exosomes are membrane-bound vesicles produced by many types of cells (21,22). Exosomes contain classical membrane marker proteins such as tetraspanins, adhesion proteins, and metalloproteinases that distinguish them from other vesicular structures such as apoptotic vesicles (23).…”

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confidence: 99%

Exosomes from HIV-1-infected Cells Stimulate Production of Pro-inflammatory Cytokines through Trans-activating Response (TAR) RNA

Sampey

Saifuddin

Schwab

et al. 2016

Journal of Biological Chemistry

178

273

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HIV-1 infection results in a chronic illness because longterm highly active antiretroviral therapy can lower viral titers to an undetectable level. However, discontinuation of therapy rapidly increases virus burden. Moreover, patients under highly active antiretroviral therapy frequently develop various metabolic disorders, neurocognitive abnormalities, and cardiovascular diseases. We have previously shown that exosomes containing trans-activating response (TAR) element RNA enhance susceptibility of undifferentiated naive cells to HIV-1 infection. This study indicates that exosomes from HIV-1-infected primary cells are highly abundant with TAR RNA as detected by RT-real time PCR. Interestingly, up to a million copies of TAR RNA/l were also detected in the serum from HIV-1-infected humanized mice suggesting that TAR RNA may be stable in vivo. Incubation of exosomes from HIV-1-infected cells with primary macrophages resulted in a dramatic increase of proinflammatory cytokines, IL-6 and TNF-␤, indicating that exosomes containing TAR RNA could play a direct role in control of cytokine gene expression. The intact TAR molecule was able to bind to PKR and TLR3 effectively, whereas the 5 and 3 stems (TAR microRNAs) bound best to TLR7 and -8 and none to PKR. Binding of TAR to PKR did not result in its phosphorylation, and therefore, TAR may be a dominant negative decoy molecule in cells. The TLR binding through either TAR RNA or TAR microRNA potentially can activate the NF-B pathway and regulate cytokine expression. Collectively, these results imply that exosomes containing TAR RNA could directly affect the proinflammatory cytokine gene expression and may explain a possible mechanism of inflammation observed in HIV-1-infected patients under cART.

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Exosomes as intercellular signalosomes and pharmacological effectors

Cited by 476 publications

References 104 publications

HIV-1 incorporation of host-cell–derived glycosphingolipid GM3 allows for capture by mature dendritic cells

HIV-1 incorporation of host-cell–derived glycosphingolipid GM3 allows for capture by mature dendritic cells

Exosomes isolated from plasma of glioma patients enrolled in a vaccination trial reflect antitumor immune activity and might predict survival

Exosomes from HIV-1-infected Cells Stimulate Production of Pro-inflammatory Cytokines through Trans-activating Response (TAR) RNA

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