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

Spivak, Adam M.; Larragoite, Erin T.; Coletti, McKenna K L; Macedo, Amanda B.; Martins, Laura J.; Bosque, Alberto; Planelles, Vicente

doi:10.1186/s12977-016-0319-0

Cited by 30 publications

(35 citation statements)

References 37 publications

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“…However, PKC agonists are known to induce T cell activation [21] and deleterious cytokines [22, 35]. Previous reports have demonstrated that LRAs can be combined with a second pharmacological agent to suppress deleterious pro-inflammatory cytokines induced upon treatment with PKC agonists [22] and TCR stimulation [23]. HDACi such as SAHA [24, 26], Trichostatin A [25], and Nicotinamide [25] have been shown to reduce pro-inflammatory cytokines in the context of graft-versus-host disease [24], rheumatoid arthritis [25], and LPS-stimulated human PBMCs [26].…”

Section: Discussionmentioning

confidence: 99%

“…Spivak et al . [22] first demonstrated that latency reversal with PKC agonist Ingenol-3,20-dibenzoate used in combination with a second pharmacological agent, Ruxolitinib, an FDA approved Janus Kinase (JAK) inhibitor, to suppress deleterious pro-inflammatory cytokine secretion, led to potent reactivation of latent HIV-1 and suppression of pro-inflammatory cytokine secretion induced by Ingenol compounds. Additionally, Rapamycin, an inhibitor of mTOR, has been shown to reduce pro-inflammatory cytokine secretion induced upon reactivation of latent HIV-1 with αCD3/αCD28 [23].…”

Section: Introductionmentioning

confidence: 99%

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Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation

Larragoite

Martins

Spivak

et al. 2017

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IntroductionThough antiretroviral therapy has led to viral suppression and increased quality of life for patients living with HIV-1, strategies to eliminate the HIV-1 latent reservoir are still necessary to eliminate HIV. Latency reversal with superior latency reversal agents (LRAs) such as protein kinase C (PKC) agonists is a promising strategy for unveiling and eliminating the latent HIV-1 reservoir. However, PKC agonists induce T cell activation and deleterious pro- inflammatory cytokine production. Secondary pharmacological agents combined with LRAs have been previously shown to reduce deleterious pro-inflammatory cytokine secretion without inhibiting HIV-1 viral reactivation. Histone deacetylase inhibitors (HDACi) are also known for inhibiting deleterious pro-inflammatory cytokines in the context of graft-versus-host disease and rheumatoid arthritis in addition to being known to synergize with PKC agonists. In this study we investigated whether HDACi and other epigenetic modifiers could decrease PKC- induced pro-inflammatory cytokines secretion while simultaneously synergizing with the PKC agonists Ingenol-3,20-dibenzoate, to enhance latency reversal.MethodsWe screened an epigenetic modifier library in health donor human peripheral blood mononuclear cells (PBMCs) to identify compounds (‘hits’) that reduced intracellular IL-6 pro-inflammatory cytokine production induced by PKC agonist Ingenol-3,20-dibenzoate. We then further tested reducers of intracellular IL-6 (‘hits’) for their ability to synergize with Ingenol-3,20-dibenzoate in the J-LAT 10.6 model of HIV-1 latency. The most promising epigenetic modifier from both screens, the HDACi Panobinostat, was then further tested for its ability to reduce pro-inflammatory cytokines and synergize with Ingenol-3,20-dibenzoate.ResultsWe show that co-treatment with Ingenol-3,20-dibenzoate and Panobinostat reduces pro-inflammatory cytokines and enhances latency reversal in vitro. Panobinostat suppressed pro-inflammatory cytokine production when combined with Ingenol-3,20- dibenzoate ex vivo when using aviremic patient cells, but antagonized Ingenol-3,20-dibenzoate dependent latency reversal ex vivo.ConclusionThe combination of Panobinostat and Ingenol-3,20-dibenzoate reduces deleterious cytokine production but is not a suitable latency reversal combination therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation

Larragoite

Martins

Spivak

et al. 2017

Preprint

Self Cite

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“…Our laboratory recently demonstrated that the FDA-approved Janus kinase (JAK) inhibitor ruxolitinib significantly decreases pro-inflammatory cytokine release from resting CD4 + T cells and PBMCs from aviremic HIV-1 infected participants, but does not affect latency reversal induced by ingenol-3,20-dibenzoate(58). Martin and colleagues demonstrated that blocking MTORC1, a signaling complex that controls cellular metabolism and activation, using the FDA-approved immunosuppressant rapamycin (also known as sirolimus), could decrease cytokine release and cell proliferation in the setting of T cell activation via CD3 and CD28 antibodies(59).…”

Section: Side Effects Of T Cell Activating Agents: Mitigating Pro-infmentioning

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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“…If studies with PKC agonists move forward, several approaches may mitigate toxicities of higher PKC agonist dosing. These include administering drugs that target PKC isoforms that induce proviral gene expression but not proinflammatory cytokines, as well as drugs such as the JAK inhibitor ruxolitinib (Spivak et al 2016) or mTOR inhibitors (Martin et al 2017) that reduce cytokine production following T cell activation without compromising the induction of proviral gene expression. The precise effects of these immune-suppressants in HIV-1 latency reversal continue to be characterized (Besnard et al 2016).…”

Section: Latency Reversing Strategiesmentioning

confidence: 99%

Targeting the Latent Reservoir for HIV-1

2018

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Antiretroviral therapy can effectively block HIV-1 viral replication and prevent or reverse immunodeficiency in HIV-1-infected individuals. However, viral replication resumes within weeks of treatment interruption. The major barrier to cure is a small pool of resting memory CD4+ T cells that harbor latent HIV-1 proviruses. This latent reservoir is now the focus of an intense international research effort. We describe how the reservoir is established, challenges involved in eliminating it, and pharmacologic and immunologic strategies for targeting this reservoir. The development of a successful cure strategy will likely require understanding the mechanisms that maintain HIV-1 proviruses in a latent state and pathways that drive the proliferation of infected cells, which slows reservoir decay. In addition, cure will require the development of effective immunologic approaches to eliminating infected cells. There is renewed optimism about the prospect of a cure, and the interventions discussed here may pave the way.

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

Cited by 30 publications

References 37 publications

Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation

Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation

Novel Latency Reversal Agents for HIV-1 Cure

Targeting the Latent Reservoir for HIV-1

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