title: 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.
abstract: 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.
authors.forename: Annie
authors.initials: A
authors.lastname: Bernier
authors.forename: Aurélie
authors.initials: A
authors.lastname: Cleret-Buhot
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Goulet
authors.forename: Patricia
authors.initials: P
authors.lastname: Monteiro
authors.forename: Annie
authors.initials: A
authors.lastname: Gosselin
authors.forename: Sandrina
authors.initials: S
authors.lastname: DaFonseca
authors.forename: Vanessa Sue
authors.initials: VS
authors.lastname: Wacleche
authors.forename: Mohammad-Ali
authors.initials: MA
authors.lastname: Jenabian
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Routy
authors.forename: Cécile
authors.initials: C
authors.lastname: Tremblay
authors.affiliation: Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Faculty of Medicine, Montreal Quebec, Canada. petronela.ancuta@umontreal.ca.
authors.forename: Petronela
authors.initials: P
authors.lastname: Ancuta
mesh_terms: D002478:Cells, Cultured; D018618:Echocardiography, Doppler, Color; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology; D047495:PPAR gamma / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology* / Q000821:virology; D058504:Th17 Cells / Q000276:immunology* / Q000821:virology; D014779:Virus Replication
chemical_list: D047495:PPAR gamma