TY - JOUR
T1 - Transcriptional profiling reveals molecular signatures associated with HIV permissiveness in th1th17 cells and identifies peroxisome proliferator-activated receptor gamma as an intrinsic negative regulator of viral replication
AU - Bernier, Annie
AU - Cleret-Buhot, Aurélie
AU - Zhang, Yuwei
AU - Goulet, Jean Philippe
AU - Monteiro, Patricia
AU - Gosselin, Annie
AU - DaFonseca, Sandrina
AU - Wacleche, Vanessa S.
AU - Jenabian, Mohammad Ali
AU - Routy, Jean Pierre
AU - Tremblay, Cécile
AU - Ancuta, Petronela
N1 - Funding Information:
Boulassel, Mr. M. Legault, and Mrs. V. Lafontaine for sample management, and Dr. C. Aiken, Dr. D. Gabuzda, Dr. J. Pomerantz, and Dr. M. Trembay for their gift of HIV plasmids. The authors also thank Ms. M. Savall for ELISA assays, Drs. N. Chomont and M. El-Far for critical reading of the manuscript and valuable discussions. Finally, the authors acknowledge human donors for their precious gift of leukapheresis essential to this work. This work was supported in part by grants from the Canadian Institutes of Health Research (CIHR) (MOP-82849; MOP-114957), Fondation du CHUM, Fonds de Recherche du Québec-Santé (FRQ-S), the French Institut National de la Santé et de la Recherche Médicale (INSERM), Agence Nationale de Recherche sur le SIDA (ANRS) and Fondation de France to PA; and infrastructure funding from the Canadian Foundation for Innovation to CT and PA. This work was also supported in part by the CIHR (grant #103230), the CIHR Canadian HIV Trials Network (CTN #247), the FRQ-S/AIDS and Infectious Diseases Network, Québec, Canada. PA was supported by New Investigator Awards from FRQ-S and INSERM. PM was supported by Postdoctoral Fellowships from the ANRS and FRQ-S. VSW was supported by a CIHR Doctoral Fellowship. MAJ is supported by a CANFAR/CTN Postdoctoral Fellowship Award. JPR holds a Louis Lowenstein Chair in Hematology and Oncology, McGill University. CT is a FRQ-S Scholar and holds a Pfizer/Université de Montréal Chair in HIV translational research. Core facilities were supported by the Fondation du CHUM and the FRQ-S/AIDS and Infectious Diseases Network. The new affiliation for AB is McGill University, Montréal, Qc, Canada.
PY - 2013/12/21
Y1 - 2013/12/21
N2 - Background: We 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.Results: Exposure 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.Conclusions: Thus, 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.
AB - Background: We 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.Results: Exposure 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.Conclusions: Thus, 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.
KW - CD4+ T-cells
KW - HIV
KW - PPARγ
KW - Th1
KW - Th1Th17
KW - cDNA microarrays
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U2 - 10.1186/1742-4690-10-160
DO - 10.1186/1742-4690-10-160
M3 - Article
C2 - 24359430
AN - SCOPUS:84890538169
SN - 1742-4690
VL - 10
JO - Retrovirology
JF - Retrovirology
IS - 1
M1 - 160
ER -