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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2017

Open Access 01-12-2017 | Research

Contrasting effect of the latency-reversing agents bryostatin-1 and JQ1 on astrocyte-mediated neuroinflammation and brain neutrophil invasion

Authors: Alizé Proust, Corinne Barat, Mathieu Leboeuf, Jean Drouin, Michel J. Tremblay

Published in: Journal of Neuroinflammation | Issue 1/2017

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Abstract

Background

Despite effectiveness of the combined antiretroviral therapy, HIV-1 persists in long-lived latently infected cells. Consequently, new therapeutic approaches aimed at eliminating this latent reservoir are currently being developed. A “shock and kill” strategy using latency-reversing agents (LRA) to reactivate HIV-1 has been proposed. However, the impact of LRA on the central nervous system (CNS) remains elusive.

Methods

We used human fetal astrocytes and investigated the effects of several LRA on their functional and secretory activities. Astrocytes were infected with VSV-G-pseudotyped HIV-1 before treatment with various blood-brain barrier (BBB)-permeable LRA at subcytotoxic doses, which allow HIV-1 reactivation based on previous in vitro and clinical studies. Cells and supernatants were then used to evaluate effects of infection and LRA on (i) viability and metabolic activity of astrocytes using a colorimetric MTS assay; (ii) chemokines and proinflammatory cytokines secretion and gene expression by astrocytes using ELISA and RT-qPCR, respectively; (iii) expression of complement component 3 (C3), a proxy for astrogliosis, by RT-qPCR; (iv) glutamate uptake capacity by a fluorometric assay; and (v) modulation of neutrophil transmigration across an in vitro BBB model.

Results

We demonstrate that bryostatin-1 induces secretion of chemokines CCL2 and IL-8 and proinflammatory cytokines IL-6 and GM-CSF, whereas their production is repressed by JQ1. Bryostatin-1 also increases expression of complement component 3 and perturbs astrocyte glutamate homeostasis. Lastly, bryostatin-1 enhances transmigration of neutrophils across an in vitro blood-brain barrier model and induces formation of neutrophil extracellular traps.

Conclusions

These observations highlight the need to carefully assess the potential harmful effect to the CNS when selecting LRA for HIV-1 reactivation strategies.
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Metadata
Title
Contrasting effect of the latency-reversing agents bryostatin-1 and JQ1 on astrocyte-mediated neuroinflammation and brain neutrophil invasion
Authors
Alizé Proust
Corinne Barat
Mathieu Leboeuf
Jean Drouin
Michel J. Tremblay
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-017-1019-y

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