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.
Highlights
We previously demonstrated that primary Th1Th17 cells are highly permissive to HIV-1, whereas Th1 cells are relatively resistant
We previously reported that: (i) Th1Th17 cells are highly permissive to replication-competent R5 and X4 HIV strains, while Th1 cells are relatively resistant; (ii) CCR6+ T-cells are major cellular targets of infection in vivo; and that (iii) the frequency of Th1Th17 but not Th1 cells is dramatically reduced in HIV-infected subjects vs. uninfected controls, with viral suppressive antiretroviral therapies (ART) being inefficient in restoring Th1Th17 paucity [31]
Superior HIV permissiveness in Th1Th17 vs. Th1 cells upon exposure to replication-competent and single-round viruses The increased expression of CCR5 on Th1Th17 vs. Th1 cells [31] suggests a superior ability of Th1Th17 cells to support HIV entry
Summary
We previously demonstrated that primary Th1Th17 cells are highly permissive to HIV-1, whereas Th1 cells are relatively resistant. Several other HDFs acting at post-entry levels were identified in the last years using genome-wide RNA interference screenings in HeLa [21,22], 293 T [23] and Jurkat cell lines [24] and other high throughput techniques [25]. These studies revealed large lists of HDFs with very limited overlap when transcripts were analyzed individually [25,26]. Some well known permissiveness factors (e.g., cyclophilin A, LEDGF/ p75) were not identified in these screens [25], suggesting that many other factors important for HIV permissiveness remain to be identified, especially in primary CD4+ T-cells
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