title: Temporal transcriptional response to latency reversing agents identifies specific factors regulating HIV-1 viral transcriptional switch.
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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Narasimhan J
authors.initials: NJ
authors.lastname: Venkatachari
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA. jmz40@pitt.edu.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Zerbato
authors.affiliation: Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, PA, 15217, USA. sj1@cs.cmu.edu.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Jain
authors.affiliation: 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.
authors.forename: Allison E
authors.initials: AE
authors.lastname: Mancini
authors.affiliation: Molecular Biology Information Service, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA. ansuman@pitt.edu.
authors.forename: Ansuman
authors.initials: A
authors.lastname: Chattopadhyay
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA. nps2@pitt.edu.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sluis-Cremer
authors.affiliation: Computer Science Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, 15217, USA. zivbj@cs.cmu.edu.
authors.forename: Ziv
authors.initials: Z
authors.lastname: Bar-Joseph
authors.affiliation: 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.
authors.forename: Velpandi
authors.initials: V
authors.lastname: Ayyavoo
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000502:physiology / Q000821:virology; D020869:Gene Expression Profiling / Q000379:methods; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D019169:Jurkat Cells; D008297:Male; D010703:Phorbol Esters / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D049490:Systems Biology / Q000379:methods; D014409:Tumor Necrosis Factor-alpha; D014775:Virus Activation / Q000187:drug effects* / Q000235:genetics*; D017735:Virus Latency / Q000187:drug effects / Q000235:genetics*; D000077337:Vorinostat
chemical_list: D006877:Hydroxamic Acids; D010703:Phorbol Esters; D014409:Tumor Necrosis Factor-alpha; D000077337:Vorinostat; C070999:prostratin