title: Janus kinase inhibition suppresses PKC-induced cytokine release without affecting HIV-1 latency reversal ex vivo.
abstract: BACKGROUND
  Despite the durable viral suppression afforded by antiretroviral therapy, HIV-1 eradication will require strategies to target latently infected cells that persist in infected individuals. Protein kinase C (PKC) activation is a promising strategy to reactivate latent proviruses and allow for subsequent recognition and clearance of infected cells by the immune system. Ingenol derivatives are PKC agonists that induce latency reversal but also lead to T cell activation and the release of pro-inflammatory cytokines, which would be undesirable in vivo. In this work, we sought to identify compounds that would suppress pro-inflammatory cytokine production in the context of PKC activation.
  
  
  METHODS
  We performed an in vitro screen to identify compounds that could dampen pro-inflammatory cytokine release associated with T cell activation, using IL-6 as a model cytokine. We then tested the ability of the most promising screening hit, the FDA-approved Janus Kinase (JAK) inhibitor ruxolitinib, to diminish release of multiple cytokines and its effect on latency reversal using cells from HIV-1-positive, aviremic participants.
  
  
  RESULTS
  We demonstrate that co-administration of ruxolitinib with ingenol-3,20-dibenzoate significantly reduces pro-inflammatory cytokine release without impairing latency reversal ex vivo.
  
  
  CONCLUSIONS
  The combination of ingenol compounds and JAK inhibition represents a novel strategy for HIV-1 eradication.
authors.affiliation: Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Adam M
authors.identifier: http://orcid.org/0000-0003-1815-7893
authors.initials: AM
authors.lastname: Spivak
authors.affiliation: Department of Pathology, University of Utah School of Medicine, Emma Eccles Jones Medical Research Building Room 2520, 15 North Medical Drive East, Salt Lake City, UT, 84112, USA.
authors.forename: Erin T
authors.initials: ET
authors.lastname: Larragoite
authors.affiliation: Department of Pathology, University of Utah School of Medicine, Emma Eccles Jones Medical Research Building Room 2520, 15 North Medical Drive East, Salt Lake City, UT, 84112, USA.
authors.forename: McKenna L
authors.initials: ML
authors.lastname: Coletti
authors.affiliation: Department of Pathology, University of Utah School of Medicine, Emma Eccles Jones Medical Research Building Room 2520, 15 North Medical Drive East, Salt Lake City, UT, 84112, USA.
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Macedo
authors.affiliation: Department of Pathology, University of Utah School of Medicine, Emma Eccles Jones Medical Research Building Room 2520, 15 North Medical Drive East, Salt Lake City, UT, 84112, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Martins
authors.affiliation: Department of Pathology, University of Utah School of Medicine, Emma Eccles Jones Medical Research Building Room 2520, 15 North Medical Drive East, Salt Lake City, UT, 84112, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bosque
authors.affiliation: Department of Pathology, University of Utah School of Medicine, Emma Eccles Jones Medical Research Building Room 2520, 15 North Medical Drive East, Salt Lake City, UT, 84112, USA. vicente.planelles@path.utah.edu.
authors.forename: Vicente
authors.initials: V
authors.lastname: Planelles
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology*; D016207:Cytokines / Q000378:metabolism*; D004224:Diterpenes / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D057166:High-Throughput Screening Assays; D006801:Humans; D015850:Interleukin-6 / Q000032:analysis; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D008213:Lymphocyte Activation; D009570:Nitriles; D011493:Protein Kinase C / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines; D014775:Virus Activation; D017735:Virus Latency
chemical_list: D019380:Anti-HIV Agents; D016207:Cytokines; D004224:Diterpenes; C508600:IL6 protein, human; D015850:Interleukin-6; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C011875:ingenol dibenzoate; C540383:ruxolitinib; D053612:Janus Kinases; D011493:Protein Kinase C; C008125:ingenol
keywords: HIV; Ingenol; Janus kinase inhibition; Ruxolitinib; Viral latency