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Identification of novel HIV-1 dependency factors in primary CCR4+CCR6+Th17 cells via a genome-wide transcriptional approach
- Source :
- Retrovirology
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
Abstract
- Background 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. Results 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. Conclusions 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. Electronic supplementary material The online version of this article (doi:10.1186/s12977-015-0226-9) contains supplementary material, which is available to authorized users.
- Subjects :
- Male
Permissiveness
Protein Tyrosine Phosphatase, Non-Receptor Type 13
HIV Infections
Virus Replication
PTPN13
NF-κB
Transcriptome
0302 clinical medicine
T-Lymphocyte Subsets
RNA interference
Cells, Cultured
0303 health sciences
NF-kappa B
hemic and immune systems
3. Good health
Cell biology
Infectious Diseases
medicine.anatomical_structure
Female
RNA Interference
MAP3K4
TCR
Adult
Receptors, CCR6
Receptors, CCR4
CD96
T cell
Receptors, Antigen, T-Cell
chemical and pharmacologic phenomena
Biology
MAP Kinase Kinase Kinase 4
03 medical and health sciences
Virology
medicine
Humans
Immunity, Mucosal
030304 developmental biology
Research
Gene Expression Profiling
T-cell receptor
HIV-1 dependency factors
Th1 Cells
Gene expression profiling
Viral replication
Immunology
HIV-1
Th17 Cells
Immunologic Memory
Human Th17 cells
030215 immunology
Subjects
Details
- ISSN :
- 17424690
- Volume :
- 12
- Database :
- OpenAIRE
- Journal :
- Retrovirology
- Accession number :
- edsair.doi.dedup.....546c0f894c53e90d1e5634d6178e1eba