Targeting NF-κB Signaling with Protein Kinase C Agonists As an Emerging Strategy for Combating HIV Latency

Jiang, Guochun; Dandekar, Satya

doi:10.1089/aid.2014.0199

Cited by 118 publications

(121 citation statements)

References 62 publications

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“…hTNF-␣ acts by triggering intracellular signals that stabilize the NF-B transcription factor, allowing nucleus translocation. Once in the nucleus, NF-B can bind to the HIV-1 LTR region and promote HIV-1 transcription (38,39). In contrast, the RMD mechanism of action is focused on inhibiting HDACs that repress the HIV-1 LTR and help to initiate viral transcription (15).…”

Section: Resultsmentioning

confidence: 99%

Kinetics of HIV-1 Latency Reversal Quantified on the Single-Cell Level Using a Novel Flow-Based Technique

Martrus

Niehrs

Cornelis

et al. 2016

J Virol

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O ne major obstacle toward an effective human immunodeficiency virus type 1 (HIV-1) cure is the establishment of a pool of long-lived latently infected cells early after infection (1). Using the rhesus macaque model of simian immunodeficiency virus (SIV) infection, it was recently shown that latent reservoirs could be seeded as early as 3 days after SIV exposure and before the detection of viremia in blood (2). The vast majority of cells infected with HIV-1 will die as a consequence of the infection or will be eliminated by the immune system. A minority of infected cells, however, turns into latently infected resting cells. These cells can either be reactivated and release de novo HIV-1 particles (3) or persist and homeostatically proliferate as long-lived memory T cells (4, 5). While current antiretroviral treatments (ARTs) can efficiently suppress HIV-1 replication and have dramatically improved the life expectancy and life quality of infected individuals, ART cannot eradicate the latent viral reservoir.Several different biological processes have been described to maintain latency in HIV-1-infected cells. Host transcription factors (TFs) such as nuclear factor kappa light-chain enhancer of activated B cells (NF-B) have multiple binding sites in the 5= long terminal repeat (LTR) of the HIV-1 genome, and their binding has been demonstrated to be necessary to initiate HIV-1 transcription (6). Sequestration of these TFs in the cytoplasm is one of the mechanisms enabling viral latency (7). Another described HIV-1 latency mechanism involves histone deacetylase (HDAC)-mediated epigenetic silencing (8). During latency establishment, HDAC molecules are recruited toward the 5= LTR of HIV-1 (9, 10) and therefore maintain the LTR in a repressed state (11). Several HDAC inhibitors (HDACis) targeting HDAC molecules have been tested for their ability to reactivate latently HIV-1-infected cells, including vorinostat, panobinostat, entinostat, and romidepsin (RMD). These HDACis proved to efficiently induce HIV-1 expression in latently infected resting CD4 ϩ T cells from HIV-1-infected individuals (8,12,13). RMD, a drug that has been used for the treatment of peripheral T-cell lymphoma,

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Section: Resultsmentioning

confidence: 99%

Kinetics of HIV-1 Latency Reversal Quantified on the Single-Cell Level Using a Novel Flow-Based Technique

Martrus

Niehrs

Cornelis

et al. 2016

J Virol

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“…NF-κB is free to enter the nucleus and bind to cognate binding sites in the viral LTR, inducing viral transcription. The role of targeting PKC-NF-κB signaling as a means to reactivate latent HIV-1 is shown in the Figure and has been reviewed in detail(29; 30). Among protein kinase C agonists, three chemical families are under active study: phorbol esters, including phorbol 12-myristate 13-acetate (PMA), prostratin and 12-deoxyphorbol 13-phenylacetate (DPP); macrocyclic lactones including bryostatin-1 and analogs; and diterpenes, which include ingenol compounds.…”

Section: T Cell Activating Agentsmentioning

confidence: 99%

Novel Latency Reversal Agents for HIV-1 Cure

2018

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Antiretroviral therapy (ART) has rendered HIV-1 infection a treatable illness, however ART is not curative due to the persistence of replication-competent, latent proviruses in long-lived resting T cells. Strategies that target these latently infected cells and allow for immune recognition and clearance of this reservoir will be necessary to eradicate HIV-1 in infected individuals. This review describes current pharmacologic approaches to reactivate the latent reservoir in a manner that infected cells can be recognized and targeted, with the ultimate goal of achieving an HIV-1 cure.

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“…Recent studies have identified the efficacy of PKC agonists including bryostatin-1 and ingenol derivatives in combination with LRAs from other mechanistic classes in vitro [12, 19–21] as well as in vivo in a non-human primate model [22]. Activation of NF-kB signaling is thought to be the mechanism by which PKC agonists reactivate latent HIV-1 provirus [23, 24]. Cellular PKC isoforms activate transcription factors including NF-kB, AP-1 and NF-AT leading to T cell activation [25–28].…”

Section: Introductionmentioning

confidence: 99%

Janus kinase inhibition suppresses PKC-induced cytokine release without affecting HIV-1 latency reversal ex vivo

et al. 2016

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BackgroundDespite 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.Design and methodsWe 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.ResultsWe demonstrate that co-administration of ruxolitinib with ingenol-3,20-dibenzoate significantly reduces pro-inflammatory cytokine release without impairing latency reversal ex vivo.ConclusionThe combination of ingenol compounds and JAK inhibition represents a novel strategy for HIV-1 eradication.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0319-0) contains supplementary material, which is available to authorized users.

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Targeting NF-κB Signaling with Protein Kinase C Agonists As an Emerging Strategy for Combating HIV Latency

Cited by 118 publications

References 62 publications

Kinetics of HIV-1 Latency Reversal Quantified on the Single-Cell Level Using a Novel Flow-Based Technique

Kinetics of HIV-1 Latency Reversal Quantified on the Single-Cell Level Using a Novel Flow-Based Technique

Novel Latency Reversal Agents for HIV-1 Cure

Janus kinase inhibition suppresses PKC-induced cytokine release without affecting HIV-1 latency reversal ex vivo

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