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Retrovirology. 2015 Oct 6;12:85. doi: 10.1186/s12977-015-0211-3.

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

Author information

1
Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh/GSPH, Room A435, Crabtree Hall, 130 DeSoto Street, Pittsburgh, PA, 15261, USA. njv12@pitt.edu.
2
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA. jmz40@pitt.edu.
3
Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, PA, 15217, USA. sj1@cs.cmu.edu.
4
Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh/GSPH, Room A435, Crabtree Hall, 130 DeSoto Street, Pittsburgh, PA, 15261, USA. aem80@pitt.edu.
5
Molecular Biology Information Service, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA. ansuman@pitt.edu.
6
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA. nps2@pitt.edu.
7
Computer Science Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, 15217, USA. zivbj@cs.cmu.edu.
8
Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh/GSPH, Room A435, Crabtree Hall, 130 DeSoto Street, Pittsburgh, PA, 15261, USA. velpandi@pitt.edu.

Abstract

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-α, 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.

PMID:
26438393
PMCID:
PMC4594640
DOI:
10.1186/s12977-015-0211-3
[Indexed for MEDLINE]
Free PMC Article

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