Transcriptional profiling reveals molecular signatures associated with HIV permissiveness in Th1Th17 cells and identifies Peroxisome Proliferator-Activated Receptor Gammaas an intrinsic negative regulator of viral replicationReportar como inadecuado




Transcriptional profiling reveals molecular signatures associated with HIV permissiveness in Th1Th17 cells and identifies Peroxisome Proliferator-Activated Receptor Gammaas an intrinsic negative regulator of viral replication - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Retrovirology

, 10:160

First Online: 21 December 2013Received: 29 August 2013Accepted: 10 December 2013

Abstract

BackgroundWe previously demonstrated that primary Th1Th17 cells are highly permissive to HIV-1, whereas Th1 cells are relatively resistant. Molecular mechanisms underlying these differences remain unknown.

ResultsExposure to replication competent and single-round VSV-G pseudotyped HIV strains provide evidence that superior HIV replication in Th1Th17 vs. Th1 cells was regulated by mechanisms located at entry and post-entry levels. Genome-wide transcriptional profiling identified transcripts upregulated n = 264 and downregulated n = 235 in Th1Th17 vs. Th1 cells p-value < 0.05; fold change cut-off 1.3. Gene Set Enrichment Analysis revealed pathways enriched in Th1Th17 nuclear receptors, trafficking, p38-MAPK, NF-κB, p53-Ras, IL-23 vs. Th1 cells proteasome, interferon α-β. Differentially expressed genes were classified into biological categories using Gene Ontology. Th1Th17 cells expressed typical Th17 markers IL-17A-F, IL-22, CCL20, RORC, IL-26, IL-23R, CCR6 and transcripts functionally linked to regulating cell trafficking CEACAM1, MCAM, activation CD28, CD40LG, TNFSF13B, TNFSF25, PTPN13, MAP3K4, LTB, CTSH, transcription PPARγ, RUNX1, ATF5, ARNTL, apoptosis FASLG, and HIV infection CXCR6, FURIN. Differential expression of CXCR6, PPARγ, ARNTL, PTPN13, MAP3K4, CTSH, SERPINB6, PTK2, and ISG20 was validated by RT-PCR, flow cytometry and-or confocal microscopy. The nuclear receptor PPARγ was preferentially expressed by Th1Th17 cells. PPARγ RNA interference significantly increased HIV replication at levels post-entry and prior HIV-DNA integration. Finally, the activation of PPARγ pathway via the agonist Rosiglitazone induced the nuclear translocation of PPARγ and a robust inhibition of viral replication.

ConclusionsThus, transcriptional profiling in Th1Th17 vs. Th1 cells demonstrated that HIV permissiveness is associated with a superior state of cellular activation and limited antiviral properties and identified PPARγ as an intrinsic negative regulator of viral replication. Therefore, triggering PPARγ pathway via non-toxic agonists may contribute to limiting covert HIV replication and disease progression during antiretroviral treatment.

KeywordsHIV CD4 T-cells Th1Th17 Th1 cDNA microarrays PPARγ Electronic supplementary materialThe online version of this article doi:10.1186-1742-4690-10-160 contains supplementary material, which is available to authorized users.

Annie Bernier, Aurélie Cleret-Buhot, Yuwei Zhang contributed equally to this work.

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Autor: Annie Bernier - Aurélie Cleret-Buhot - Yuwei Zhang - Jean-Philippe Goulet - Patricia Monteiro - Annie Gosselin - Sandrina 

Fuente: https://link.springer.com/



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