Differential effects of phorbol-13-monoesters on human immunodeficiency virus reactivation

Márquez, Nieves; Calzado, Marco A.; Sánchez‐Duffhues, Gonzalo; Perez, M. P. Burkhardt; Minassi, Alberto; Pagani, Alberto; Appendino, Giovanni; Díaz, Laura; Muñoz‐Fernández, María Ángeles; Muñóz, Eduardo

doi:10.1016/j.bcp.2007.12.004

Cited by 71 publications

(80 citation statements)

References 37 publications

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“…The J-Lat model for HIV-1 latency, containing either a minimal HIV-1 minigenome or a recombinant full-length virus (38), is useful for the study of the determinants of postintegration latency associated with distinct integration events (4, 5, 22-24, 41, 48, 49, 59, 80) or to investigate the reactivating potential of several agents (21,52,57,62,66,68,79,81,83). Latency is established due to transcriptional silencing (i.e., the repression of the integrated HIV-1 promoter).…”

Section: Discussionmentioning

confidence: 99%

Combination of Biological Screening in a Cellular Model of Viral Latency and Virtual Screening Identifies Novel Compounds That Reactivate HIV-1

Gallastegui

Marshall

Vidal

et al. 2012

J Virol

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e Although highly active antiretroviral therapy (HAART) has converted HIV into a chronic disease, a reservoir of HIV latently infected resting T cells prevents the eradication of the virus from patients. To achieve eradication, HAART must be combined with drugs that reactivate the dormant viruses. We examined this problem in an established model of HIV postintegration latency by screening a library of small molecules. Initially, we identified eight molecules that reactivated latent HIV. Using them as templates, additional hits were identified by means of similarity-based virtual screening. One of those hits, 8-methoxy-6-methylquinolin-4-ol (MMQO), proved to be useful to reactivate HIV-1 in different cellular models, especially in combination with other known reactivating agents, without causing T-cell activation and with lower toxicity than that of the initial hits. Interestingly, we have established that MMQO produces Jun N-terminal protein kinase (JNK) activation and enhances the T-cell receptor (TCR)/CD3 stimulation of HIV-1 reactivation from latency but inhibits CD3-induced interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF-␣) gene transcription. Moreover, MMQO prevents TCR-induced cell cycle progression and proliferation in primary T cells. The present study documents that the combination of biological screening in a cellular model of viral latency with virtual screening is useful for the identification of novel agents able to reactivate HIV-1. Moreover, we set the bases for a hypothetical therapy to reactivate latent HIV by combining MMQO with physiological or pharmacological TCR/CD3 stimulation.

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Section: Discussionmentioning

confidence: 99%

Combination of Biological Screening in a Cellular Model of Viral Latency and Virtual Screening Identifies Novel Compounds That Reactivate HIV-1

Gallastegui

Marshall

Vidal

et al. 2012

J Virol

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“…However, prostratin could inhibit HIV-1 infection in CD4 ϩ T cells at both entry and postentry steps, which may reduce the risk of new infections after latency reactivation (4,76). Finally, recent studies have identified synthetic PKC activators and HDAC inhibitors that may provide higher efficacy with reduced toxicity and cost compared to prostratin and SAHA (60,64,71,77). Thus, with the development of such new antilatency compounds, the prospects of activating latency across different subtypes and promoter mutants should be explored.…”

Section: Discussionmentioning

confidence: 99%

Combinatorial Latency Reactivation for HIV-1 Subtypes and Variants

Burnett

Lim

Calafi

et al. 2010

J Virol

115

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The eradication of HIV-1 will likely require novel clinical approaches to purge the reservoir of latently infected cells from a patient. We hypothesize that this therapy should target a wide range of latent integration sites, act effectively against viral variants that have acquired mutations in their promoter regions, and function across multiple HIV-1 subtypes. By using primary CD4؉ and Jurkat cell-based in vitro HIV-1 latency models, we observe that single-agent latency reactivation therapy is ineffective against most HIV-1 subtypes. However, we demonstrate that the combination of two clinically promising drugs-namely, prostratin and suberoylanilide hydroxamic acid (SAHA)-overcomes the limitations of single-agent approaches and can act synergistically for many HIV-1 subtypes, including A, B, C, D, and F. Finally, by identifying the proviral integration position of latent Jurkat cell clones, we demonstrate that this drug combination does not significantly enhance the expression of endogenous genes nearest to the proviral integration site, indicating that its effects may be selective.HIV-1 postintegration latency poses the greatest barrier to complete eradication of the virus from a patient (25). Latent infections have low or no transcriptional activity and fail to generate viral progeny, rendering them untreatable with current antiretroviral treatments that target only actively replicating virus (78). Moreover, latent infections, which persist in resting memory CD4 ϩ T cells with a half-life of up to 44 months (79), provide a permanent reservoir for reactivation and reseeding of the replicating virus (83). Therapeutic reactivation of latent infections, combined with antiretroviral treatments, may accelerate the depletion of latent reservoirs (reviewed in reference 29). However, such latency reactivation strategies have yielded variable results in recent clinical trials (49,80,82), underscoring the difficulties associated with purging latent infections. Therefore, the complexities of latency warrant the further development of in vitro analytical and screening assays that can model the conditions of latency and test potential therapies (9).After viral entry and integration of the viral genome into the host chromosome, the HIV 5Ј long terminal repeat (5Ј LTR) promoter recruits RNA polymerase II (RNAPII) and other host factors to regulate viral gene expression. Initially, low basal transcription generates primarily abortive transcriptsdue to the stalling of RNAPII-and a small fraction of fully elongated viral transcript that is initially spliced to generate mRNA encoding a positive regulator, the transcriptional activator (Tat) (47). Tat protein interacts with cellular positive transcriptional elongation factor B (P-TEFb) (99), and the resulting Tat-P-TEFb complex binds to the trans-activation response (TAR) element at the 5Ј end of nascent viral transcripts (3). Here, P-TEFb phosphorylates the C-terminal domain (CTD) of stalled RNAPII to enhance the efficiency of elongation (98). This Tat-mediated transactivation...

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“…However, prostratin (12-deoxyphorbol-13-acetate, 70) and DPP (12-deoxyphorbol-13-benzoate, 71) are non-tumorpromoting members of the phorbol ester family with no hydroxyl/acyl group at C12 ( Figure 10) [226,227]. Recently, the Wender group developed a five-step synthesis to prostratin and its derivatives starting from readily available phorbol (7) [226].…”

Section: Other C1 Domain Ligandsmentioning

confidence: 99%

“…However, high doses or prolonged treatments with prostratin may not be well tolerated in humans [231]. Subsequently, a series of phorbol 13-O-monoesters were shown to be effective in latent virus reactivation and to induce PKC translocation patterns typical for non-tumor promoters [227]. The marine spiroketals aplysiatoxin (72) and debromoaplysiatoxin (73) can be isolated from the sea hare Stylocheilus longicauda (Figure 10) [232].…”

Section: Other C1 Domain Ligandsmentioning

confidence: 99%

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

Gennäs

Talman²,

Yli‐Kauhaluoma³

et al. 2011

CTMC

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Protein kinase C (PKC) comprises a family of ten isoforms that play roles in diverse cellular processes such as proliferation, apoptosis and differentiation. PKC isoforms respond to Gprotein coupled receptor-and receptor tyrosine kinase-signaling via binding the second messenger diacylglycerol with C1 domains. Aberrant signaling through PKC isoforms and other C1 domain-containing proteins has been implicated in several pathological disorders.Drug discovery concerning C1 domains has exploited natural products and rationally designed compounds. Currently, molecules from several classes of C1 domain-binding compounds are in clinical trials; however, still more have the potential to enter the drug development pipeline. This review gives a summary of the recent developments in C1 domain-binding compounds.

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Differential effects of phorbol-13-monoesters on human immunodeficiency virus reactivation

Cited by 71 publications

References 37 publications

Combination of Biological Screening in a Cellular Model of Viral Latency and Virtual Screening Identifies Novel Compounds That Reactivate HIV-1

Combination of Biological Screening in a Cellular Model of Viral Latency and Virtual Screening Identifies Novel Compounds That Reactivate HIV-1

Combinatorial Latency Reactivation for HIV-1 Subtypes and Variants

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

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