Characterization of designed, synthetically accessible bryostatin analog HIV latency reversing agents

Marsden, Matthew D.; Wu, Xiaomeng; Navab, Sara M.; Loy, Brian A.; Schrier, Adam J.; DeChristopher, Brian A.; Shimizu, Akira; Hardman, Clayton; Ho, Stephen; Ramirez, Christina M.; Wender, Paul A.; Zack, Jerome A.

doi:10.1016/j.virol.2018.05.006

Cited by 36 publications

(39 citation statements)

References 65 publications

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“…Cell surface expression of CD69, a biomarker of early T cell activation, is well known to directly correlate with PKC activity (46)(47)(48). Recent studies with bryostatin-1 and bryostatin analogs have demonstrated a direct correlation between CD69 expression and HIV-1 latency reversal in vitro (48,49). We identified a similar positive correlation between the EC 50 of synthetic ingenols for the induction of CD69 expression on primary resting CD4 ϩ T cells and the EC 50 for latency reversal in J-Lat 10.6 from experiments described above (Fig.…”

Section: Figmentioning

confidence: 99%

Synthetic Ingenols Maximize Protein Kinase C-Induced HIV-1 Latency Reversal

Spivak

Nell

Petersen

et al. 2018

Antimicrob Agents Chemother

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Antiretroviral therapy (ART) does not cure HIV-1 infection due to the persistence of proviruses in long-lived resting T cells. Strategies targeting these latently infected cells will be necessary to eradicate HIV-1 in infected individuals. Protein kinase C (PKC) activation is an effective mechanism to reactivate latent proviruses and allows for recognition and clearance of infected cells by the immune system. Several ingenol compounds, naturally occurring PKC agonists, have been described to have potent latency reversal activity. We sought to optimize this activity by synthesizing a library of novel ingenols via esterification of the C-3 hydroxyl group of the ingenol core, which itself is inactive for latency reversal. Newly synthesized ingenol derivatives were evaluated for latency reversal activity, cellular activation, and cytotoxicity alongside commercially available ingenols (ingenol-3,20-dibenzoate, ingenol 3-hexanoate, and ingenol-3-angelate) in HIV latency cell lines and resting CD4 T cells from aviremic participants. Among the synthetic ingenols that we produced, we identified several compounds that demonstrate high efficacy and represent promising leads as latency reversal agents for HIV-1 eradication.

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Section: Figmentioning

confidence: 99%

Synthetic Ingenols Maximize Protein Kinase C-Induced HIV-1 Latency Reversal

Spivak

Nell

Petersen

et al. 2018

Antimicrob Agents Chemother

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“…When 6 μM PC1 was used in combination with kansui or JQ1, HSA expression increased 2-fold over kansui or JQ1 alone ( Fig 5A and 5B , lane 5). The additive effect of PC1 and kansui or JQ1 is indicated by the dashed line on each graph, and neither double treatment surpassed this additive effect ( Fig 5A and 5B , lane 5) [ 39 ]. However, when used as a triple combination, 6 μM PC1 increased expression of HSA 3.5-fold over kansui and 2.5-fold over JQ1 ( Fig 5C , lanes 4–6).…”

Section: Resultsmentioning

confidence: 99%

Procyanidin trimer C1 reactivates latent HIV as a triple combination therapy with kansui and JQ1

Cary

Peterlin

2018

PLoS ONE

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Although anti-retroviral therapies have greatly extended the lives of HIV infected individuals, current treatments are unable to completely eliminate virally infected cells. A number of latency reversing agents have been proposed for use in a “shock and kill” strategy to reactivate latent HIV, thus making it vulnerable to killing mechanisms. Procyanidin trimer C1 (PC1) is a flavonoid found in multiple plant sources including grape, apple, and cacao, which has antioxidant and anti-inflammatory properties. We determined that PC1 reactivates latent HIV in cell line and primary cell models of HIV, through activation of the MAPK pathway. Notably, PC1 reactivates latent HIV without increasing surface markers of T cell activation. Combining several therapeutics, which activate HIV transcription through different mechanisms, is the most efficient approach to clinically reactivate latent reservoirs. We utilized PC1 (MAPK agonist), kansui (PKC agonist), and JQ1 (BET bromodomain inhibitor) in a triple combination approach to reactivate latent HIV in cell line and primary cell models of HIV latency. When used in combination, low concentrations which fail to reactivate HIV as single treatments, are effective. Thus, several mechanisms, using distinct activation pathways, act together to reactivate latent HIV.

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“…Some of the prominent LRAs currently in use in ongoing clinical trials include histone deacetylate inhibitors (HDACi) and histone methyltransferases inhibitors (HMTi), which induce HIV-1 expression by reversing epigenetic silencing (Lehrman et al, 2005;Agosto et al, 2007;Archin et al, 2012Archin et al, , 2014aDelagrèverie et al, 2016;Aid et al, 2018;Abner and Jordan, 2019). Alternatively, protein kinase C (PKC) agonists (Williams et al, 2004;Perez et al, 2010;Marsden et al, 2018) and CCR5 agonists (López-Huertas et al, 2017;Madrid-Elena et al, 2018) stimulate latent HIV-1 by activating NF-κB. The use of toll like receptor (TLR) agonists as LRAs has also been explored, as they stimulate immune signaling pathways, leading to HIV-1 expression (Thibault et al, 2009;Novis et al, 2013;Alvarez-Carbonell et al, 2017).…”

Section: Shock and Killmentioning

confidence: 99%

Measuring the Success of HIV-1 Cure Strategies

Thomas

Ruggiero

Paxton

et al. 2020

Front. Cell. Infect. Microbiol.

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HIV-1 eradication strategies aim to achieve viral remission in the absence of antiretroviral therapy (ART). The development of an HIV-1 cure remains challenging due to the latent reservoir (LR): long-lived CD4 T cells that harbor transcriptionally silent HIV-1 provirus. The LR is stable despite years of suppressive ART and is the source of rebound viremia following therapy interruption. Cure strategies such as "shock and kill" aim to eliminate or reduce the LR by reversing latency, exposing the infected cells to clearance via the immune response or the viral cytopathic effect. Alternative strategies include therapeutic vaccination, which aims to prime the immune response to facilitate control of the virus in the absence of ART. Despite promising advances, these strategies have been unable to significantly reduce the LR or increase the time to viral rebound but have provided invaluable insight in the field of HIV-1 eradication. The development and assessment of an HIV-1 cure requires robust assays that can measure the LR with sufficient sensitivity to detect changes that may occur following treatment. The viral outgrowth assay (VOA) is considered the gold standard method for LR quantification due to its ability to distinguish intact and defective provirus. However, the VOA is time consuming and resource intensive, therefore several alternative assays have been developed to bridge the gap between practicality and accuracy. Whilst a cure for HIV-1 infection remains elusive, recent advances in our understanding of the LR and methods for its eradication have offered renewed hope regarding achieving ART free viral remission.

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Characterization of designed, synthetically accessible bryostatin analog HIV latency reversing agents

Cited by 36 publications

References 65 publications

Synthetic Ingenols Maximize Protein Kinase C-Induced HIV-1 Latency Reversal

Synthetic Ingenols Maximize Protein Kinase C-Induced HIV-1 Latency Reversal

Procyanidin trimer C1 reactivates latent HIV as a triple combination therapy with kansui and JQ1

Measuring the Success of HIV-1 Cure Strategies

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