Logo image
Back
Identification of novel HIV-1 dependency factors in primary CCR4(+)CCR6(+)Th17 cells via a genome-wide transcriptional approach
Journal article   Open access   Peer reviewed

Identification of novel HIV-1 dependency factors in primary CCR4(+)CCR6(+)Th17 cells via a genome-wide transcriptional approach

Aurélie Cleret-Buhot, Yuwei Zhang, Delphine Planas, Jean-Philippe Goulet, Patricia Monteiro, Annie Gosselin, Vanessa Sue Wacleche, Cécile L Tremblay, Mohammad-Ali Jenabian, Jean-Pierre Routy, …
Retrovirology, v 12(1), pp 102-102
10 Dec 2015
DOI: https://doi.org/10.1186/s12977-015-0226-9
PMID: 26654242
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1186/s12977-015-0226-9View
Published, Version of Record (VoR) Open

Abstract

Adult Cells, Cultured Female Gene Expression Profiling HIV Infections - virology HIV-1 - physiology Humans Immunity, Mucosal Immunologic Memory Male MAP Kinase Kinase Kinase 4 - genetics MAP Kinase Kinase Kinase 4 - metabolism NF-kappa B - metabolism Protein Tyrosine Phosphatase, Non-Receptor Type 13 - genetics Protein Tyrosine Phosphatase, Non-Receptor Type 13 - metabolism Receptors, Antigen, T-Cell - genetics Receptors, Antigen, T-Cell - immunology Receptors, Antigen, T-Cell - metabolism Receptors, CCR4 - immunology Receptors, CCR6 - immunology RNA Interference T-Lymphocyte Subsets - virology Th1 Cells - immunology Th1 Cells - virology Th17 Cells - classification Th17 Cells - immunology Th17 Cells - virology Transcriptome Virus Replication
The HIV-1 infection is characterized by profound CD4(+) T cell destruction and a marked Th17 dysfunction at the mucosal level. Viral suppressive antiretroviral therapy restores Th1 but not Th17 cells. Although several key HIV dependency factors (HDF) were identified in the past years via genome-wide siRNA screens in cell lines, molecular determinants of HIV permissiveness in primary Th17 cells remain to be elucidated. In an effort to orient Th17-targeted reconstitution strategies, we investigated molecular mechanisms of HIV permissiveness in Th17 cells. Genome-wide transcriptional profiling in memory CD4(+) T-cell subsets enriched in cells exhibiting Th17 (CCR4(+)CCR6(+)), Th1 (CXCR3(+)CCR6(-)), Th2 (CCR4(+)CCR6(-)), and Th1Th17 (CXCR3(+)CCR6(+)) features revealed remarkable transcriptional differences between Th17 and Th1 subsets. The HIV-DNA integration was superior in Th17 versus Th1 upon exposure to both wild-type and VSV-G-pseudotyped HIV; this indicates that post-entry mechanisms contribute to viral replication in Th17. Transcripts significantly enriched in Th17 versus Th1 were previously associated with the regulation of TCR signaling (ZAP-70, Lck, and CD96) and Th17 polarization (RORγt, ARNTL, PTPN13, and RUNX1). A meta-analysis using the NCBI HIV Interaction Database revealed a set of Th17-specific HIV dependency factors (HDFs): PARG, PAK2, KLF2, ITGB7, PTEN, ATG16L1, Alix/AIP1/PDCD6IP, LGALS3, JAK1, TRIM8, MALT1, FOXO3, ARNTL/BMAL1, ABCB1/MDR1, TNFSF13B/BAFF, and CDKN1B. Functional studies demonstrated an increased ability of Th17 versus Th1 cells to respond to TCR triggering in terms of NF-κB nuclear translocation/DNA-binding activity and proliferation. Finally, RNA interference studies identified MAP3K4 and PTPN13 as two novel Th17-specific HDFs. The transcriptional program of Th17 cells includes molecules regulating HIV replication at multiple post-entry steps that may represent potential targets for novel therapies aimed at protecting Th17 cells from infection and subsequent depletion in HIV-infected subjects.

Metrics

12 Record Views
48 citations in Web of Science
51 citations in Scopus

Details

UN Sustainable Development Goals (SDGs)

This publication has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

InCites Highlights

Data related to this publication, from InCites Benchmarking & Analytics tool:

Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Virology
Logo image