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).
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-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.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
Metrics
Monthly Views for the past 3 years
Plum Analytics
Altmetric.com
Actions (login required)
 |
View Item |
![[img]](https://d-scholarship.pitt.edu/style/images/fileicons/text_plain.png)
![[feed]](/images/feed-icon-32x32.png){kind=icon}