In vivo activation of latent HIV with a synthetic bryostatin analog effects both latent cell "kick" and "kill" in strategy for virus eradication

Marsden, Matthew D.; Loy, Brian A.; Wu, Xiaomeng; Ramirez, Christina M.; Schrier, Adam J.; Murray, Danielle; Shimizu, Akira; Ryckbosch, Steven M.; Near, Katherine E.; Chun, Tae‐Wook; Wender, Paul A.; Zack, Jerome A.

doi:10.1371/journal.ppat.1006575

Cited by 83 publications

(97 citation statements)

References 47 publications

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“…[18] demonstrated that PKC agonists are superior LRAs, shown to reactivate latent HIV-1 across multiple models of HIV-1 latency, whereas other well characterized LRAs such as HDACi were unable to reactivate to the same extent in some models of HIV-1 latency. Additionally, PKC agonists have been shown to reactivate latent provirus and lead to cell death of HIV-1 infected cells [19]. PKC agonists are thought to reactivate latent HIV-1 though activation of NF-κB and have been shown to additionally activate AP-1 and NFAT [20].…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation

Larragoite

Martins

Spivak

et al. 2017

Preprint

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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: Introductionmentioning

confidence: 99%

Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation

Larragoite

Martins

Spivak

et al. 2017

Preprint

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“…Several humanized mouse models have been developed to study HIV-1 replication and latency (30,(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). Mice containing human CD4 T cells support both R5-and X4-tropic HIV-1 infections (reviewed in reference 45) and respond to treatment with ART, typically administered by intraperitoneal (i.p.)…”

mentioning

confidence: 99%

“…In the present study, we analyzed the latent reservoir in humanized mice using a system that takes advantage of an epitope-tagged strain of HIV-1 to deplete productively infected cells (40,42). This model revealed latent but reactivatable HIV-1 present in lymphoid tissues harvested from the mice, both with and without ART, and allowed us to analyze the contribution of specific T cell subsets to the latent reservoir.…”

mentioning

confidence: 99%

Humanized Mouse Model of HIV-1 Latency with Enrichment of Latent Virus in PD-1 ⁺ and TIGIT ⁺ CD4 T Cells

Llewellyn

Seclén

Wietgrefe

et al. 2019

J Virol

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Combination anti-retroviral drug therapy (ART) potently suppresses HIV-1 replication but does not result in virus eradication or a cure. A major contributing factor is the long-term persistence of a reservoir of latently infected cells. To study this reservoir, we established a humanized mouse model of HIV-1 infection and ART suppression based on an oral ART regimen. Similar to humans, HIV-1 levels in the blood of ART-treated animals were frequently suppressed below the limits of detection. However, the limited timeframe of the mouse model and the small volume of available samples makes it a challenging model with which to achieve full viral suppression and to investigate the latent reservoir. We therefore used an ex vivo latency reactivation assay that allows a semiquantitative measure of the latent reservoir that establishes in individual animals, regardless of whether they are treated with ART. Using this assay, we found that latently infected human CD4 T cells can be readily detected in mouse lymphoid tissues and that latent HIV-1 was enriched in populations expressing markers of T cell exhaustion, PD-1 and TIGIT. In addition, we were able to use the ex vivo latency reactivation assay to demonstrate that HIV-specific TALENs can reduce the fraction of reactivatable virus in the latently infected cell population that establishes in vivo, supporting the use of targeted nuclease-based approaches for an HIV-1 cure.

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“…However, in this study, iDCs were cultured with T cells that had been preactivated using either PHA or anti-CD3/CD28 beads. These treatments alone have been shown to reverse HIV-1 latency [184,[223][224][225][226], and thus, it is difficult to dissect the clinical relevance.…”

Section: Lra Potential Of Dcsmentioning

confidence: 99%

Role of Dendritic Cells in Exposing Latent HIV-1 for the Kill

Kristoff

Rinaldo

Mailliard

2019

Viruses

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The development of effective yet nontoxic strategies to target the latent human immunodeficiency virus-1 (HIV-1) reservoir in antiretroviral therapy (ART)-suppressed individuals poses a critical barrier to a functional cure. The 'kick and kill' approach to HIV eradication entails proviral reactivation during ART, coupled with generation of cytotoxic T lymphocytes (CTLs) or other immune effectors equipped to eliminate exposed infected cells. Pharmacological latency reversal agents (LRAs) that have produced modest reductions in the latent reservoir ex vivo have not impacted levels of proviral DNA in HIV-infected individuals. An optimal cure strategy incorporates methods that facilitate sufficient antigen exposure on reactivated cells following the induction of proviral gene expression, as well as the elimination of infected targets by either polyfunctional HIV-specific CTLs or other immune-based strategies. Although conventional dendritic cells (DCs) have been used extensively for the purpose of inducing antigen-specific CTL responses in HIV-1 clinical trials, their immunotherapeutic potential as cellular LRAs has been largely ignored. In this review, we discuss the challenges associated with current HIV-1 eradication strategies, as well as the unharnessed potential of ex vivo-programmed DCs for both the 'kick and kill' of latent HIV-1.

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In vivo activation of latent HIV with a synthetic bryostatin analog effects both latent cell "kick" and "kill" in strategy for virus eradication

Cited by 83 publications

References 47 publications

Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation

Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation

Humanized Mouse Model of HIV-1 Latency with Enrichment of Latent Virus in PD-1 ⁺ and TIGIT ⁺ CD4 T Cells

Role of Dendritic Cells in Exposing Latent HIV-1 for the Kill

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In vivo activation of latent HIV with a synthetic bryostatin analog effects both latent cell "kick" and "kill" in strategy for virus eradication

Cited by 83 publications

References 47 publications

Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation

Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation

Humanized Mouse Model of HIV-1 Latency with Enrichment of Latent Virus in PD-1 + and TIGIT + CD4 T Cells

Role of Dendritic Cells in Exposing Latent HIV-1 for the Kill

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Humanized Mouse Model of HIV-1 Latency with Enrichment of Latent Virus in PD-1 ⁺ and TIGIT ⁺ CD4 T Cells