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

Retrovirology

Petronela Ancuta⁶  Rafick-Pierre Sekaly⁴  Elias K. Haddad¹  Nicolas Chomont⁶  Mohamed El-Far⁶  Jean-Pierre Routy⁵  Mohammad-Ali Jenabian²  Cécile L. Tremblay⁶  Vanessa Sue Wacleche⁶  Annie Gosselin⁶  Patricia Monteiro⁶  Jean-Philippe Goulet³  Delphine Planas⁶  Yuwei Zhang⁶  Aurélie Cleret-Buhot⁶ 

[1] Division of infectious Diseases and HIV Medicine, Drexel University, Philadelphia, PA, USA;Département des sciences biologiques, Université du Québec à Montréal, Montreal, QC, Canada;Caprion, Montreal, QC, Canada;Center for AIDS Research, Case Western Reserve University, Cleveland, OH, USA;Division of Hematology, McGill University Health Centre, Montreal, QC, Canada;CHUM-Research Centre, 900 rue Saint-Denis, Tour Viger, R09.416, Montreal H2X 0A9, QUÉBEC, Canada

关键词: PTPN13;    MAP3K4;    NF-κB;    TCR;    HIV-1 dependency factors;    Human Th17 cells;   

Others  :  1235120
DOI  :  10.1186/s12977-015-0226-9

 received in 2015-09-15, accepted in 2015-11-22,  发布年份 2015

【 摘 要 】

Background

The HIV-1 infection is characterized byprofound 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.

【 授权许可】

   
2015 Cleret-Buhot et al.

【 图 表 】

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