TY - JOUR
T1 - Reactivation of latent HIV-1 by new semi-synthetic ingenol esters
AU - Pandeló José, Diego
AU - Bartholomeeusen, Koen
AU - da Cunha, Rodrigo Delvecchio
AU - Abreu, Celina Monteiro
AU - Glinski, Jan
AU - da Costa, Thais Barbizan Ferreira
AU - Bacchi Rabay, Ana Flávia Mello
AU - Pianowski Filho, Luiz Francisco
AU - Dudycz, Lech W.
AU - Ranga, Udaykumar
AU - Peterlin, Boris Matija
AU - Pianowski, Luiz Francisco
AU - Tanuri, Amilcar
AU - Aguiar, Renato Santana
N1 - Funding Information:
We thank Dr. Morgan Huse and Dr. Kotaro Shirakawa to gently provide the human PKC-GFP plasmids (α, δ and γ) and pEnvHIV, respectively. We also thank Dr. Ana Lucia Moraes Giannini for English review. This work was supported by research grants from Brazilian agencies CNPq (Grant nos. 480861/2011-0 , 405283/2013-0 ) and FAPERJ (Grant no. E- 26/111.267/2013 ) and Diego Pandeló José was supported by CNPq fellowship . We acknowledge funding support to UR from DST, India toward the Indo-Brazil collaboration.
PY - 2014/8
Y1 - 2014/8
N2 - 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.
AB - 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.
KW - HIV
KW - Ingenol
KW - Latency
KW - NF-kB
KW - P-TEFb
KW - PKC
KW - Resting cells
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U2 - 10.1016/j.virol.2014.05.033
DO - 10.1016/j.virol.2014.05.033
M3 - Article
C2 - 25014309
AN - SCOPUS:84907288256
SN - 0042-6822
VL - 462-463
SP - 328
EP - 339
JO - Virology
JF - Virology
IS - 1
ER -