TY  - JOUR
AU  - Venkatachari, NJ
AU  - Zerbato, JM
AU  - Jain, S
AU  - Mancini, AE
AU  - Chattopadhyay, A
AU  - Sluis-Cremer, N
AU  - Bar-Joseph, Z
AU  - Ayyavoo, V
Y2  - 2020/12/22
Y1  - 2015/10/06
SN  - 1742-4690
UR  - http://hdl.handle.net/11343/257771
AB  - 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.
LA  - eng
PB  - Springer Science and Business Media LLC
T1  - Temporal transcriptional response to latency reversing agents identifies specific factors regulating HIV-1 viral transcriptional switch.
DO  - 10.1186/s12977-015-0211-3
IS  - Retrovirology
VL  - 12
IS  - 1
SP  - 85-
L1  - /bitstream/handle/11343/257771/PMC4594640.pdf?sequence=1&isAllowed=y
ER  -