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Temporal transcriptional response to latency reversing agents identifies specific factors regulating HIV-1 viral transcriptional switch

Venkatachari, NJ and Zerbato, JM and Jain, S and Mancini, AE and Chattopadhyay, A and Sluis-Cremer, N and Bar-Joseph, Z and Ayyavoo, V (2015) Temporal transcriptional response to latency reversing agents identifies specific factors regulating HIV-1 viral transcriptional switch. Retrovirology, 12 (1).

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Abstract

© 2015 Venkatachari et al. Background: Latent HIV-1 reservoirs are identified as one of the major challenges to achieve HIV-1 cure. Currently available strategies are associated with wide variability in outcomes both in patients and CD4+ T cell models. This underlines the critical need to develop innovative strategies to predict and recognize ways that could result in better reactivation and eventual elimination of latent HIV-1 reservoirs. Results and discussion: In this study, we combined genome wide transcriptome datasets post activation with Systems Biology approach (Signaling and Dynamic Regulatory Events Miner, SDREM analyses) to reconstruct a dynamic signaling and regulatory network involved in reactivation mediated by specific activators using a latent cell line. This approach identified several critical regulators for each treatment, which were confirmed in follow-up validation studies using small molecule inhibitors. Results indicate that signaling pathways involving JNK and related factors as predicted by SDREM are essential for virus reactivation by suberoylanilide hydroxamic acid. ERK1/2 and NF-κB pathways have the foremost role in reactivation with prostratin and TNF-aα, respectively. JAK-STAT pathway has a central role in HIV-1 transcription. Additional evaluation, using other latent J-Lat cell clones and primary T cell model, also confirmed that many of the cellular factors associated with latency reversing agents are similar, though minor differences are identified. JAK-STAT and NF-κB related pathways are critical for reversal of HIV-1 latency in primary resting T cells. Conclusion: These results validate our combinatorial approach to predict the regulatory cellular factors and pathways responsible for HIV-1 reactivation in latent HIV-1 harboring cell line models. JAK-STAT have a role in reversal of latency in all the HIV-1 latency models tested, including primary CD4+ T cells, with additional cellular pathways such as NF-κB, JNK and ERK 1/2 that may have complementary role in reversal of HIV-1 latency.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Venkatachari, NJnjv12@pitt.eduNJV12
Zerbato, JMjmz40@pitt.eduJMZ40
Jain, S
Mancini, AEaem80@pitt.eduAEM80
Chattopadhyay, Aansuman@pitt.eduANSUMAN
Sluis-Cremer, Nnps2@pitt.eduNPS2
Bar-Joseph, Zzivbj@pitt.eduZIVBJ
Ayyavoo, Vvelpandi@pitt.eduVELPANDI
Date: 6 October 2015
Date Type: Publication
Journal or Publication Title: Retrovirology
Volume: 12
Number: 1
DOI or Unique Handle: 10.1186/s12977-015-0211-3
Schools and Programs: School of Medicine > Infectious Diseases and Microbiology
School of Medicine > Medicine
Refereed: Yes
Date Deposited: 09 Aug 2016 20:04
Last Modified: 02 Feb 2019 15:55
URI: http://d-scholarship.pitt.edu/id/eprint/29059

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