Reactivation of latent HIV-1 by new semi-synthetic ingenol esters

Diego Pandeló José, Koen Bartholomeeusen, Rodrigo Delvecchio da Cunha, Celina Monteiro Abreu, Jan Glinski, Thais Barbizan Ferreira da Costa, Ana Flávia Mello Bacchi Rabay, Luiz Francisco Pianowski Filho, Lech W Dudycz, Udaykumar Ranga, Boris Matija Peterlin, Luiz Francisco Pianowski, Amilcar Tanuri, Renato Santana Aguiar

Research output: Contribution to journalA2: International peer reviewed article (not A1-type)

Abstract

The ability of HIV to establish long-lived latent infection is mainly due to transcriptional silencing of viral genome in resting memory T lymphocytes. Here, we show that new semi-synthetic ingenol esters reactivate latent HIV reservoirs. Amongst the tested compounds, 3-caproyl-ingenol (ING B) was more potent in reactivating latent HIV than known activators such as SAHA, ingenol 3,20-dibenzoate, TNF-α, PMA and HMBA. ING B activated PKC isoforms followed by NF-κB nuclear translocation. As virus reactivation is dependent on intact NF-κB binding sites in the LTR promoter region ING B, we have shown that. ING B was able to reactivate virus transcription in primary HIV-infected resting cells up to 12 fold and up to 25 fold in combination with SAHA. Additionally, ING B promoted up-regulation of P-TEFb subunits CDK9/Cyclin T1. The role of ING B on promoting both transcription initiation and elongation makes this compound a strong candidate for an anti-HIV latency drug combined with suppressive HAART.

Original languageEnglish
JournalVirology
Volume462-463
Pages (from-to)328-39
Number of pages12
ISSN0042-6822
DOIs
Publication statusPublished - Aug-2014
Externally publishedYes

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