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Virology. 2014 Aug;462-463:328-39. doi: 10.1016/j.virol.2014.05.033. Epub 2014 Jul 9.

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

Author information

1
Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
2
Department of Medicine, Microbiology and Immunology, University of California at San Francisco, San Francisco, CA 94143-0703, United States.
3
PlantaAnalytica LLC, Danbury, CT 06810, United States.
4
Kyolab Laboratories, Valinhos, São Paulo 13273-105, Brazil.
5
Lex Company Research Laboratories, Shirley 01464, MA, United States.
6
Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru 560064, India.
7
Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil. Electronic address: santana@biologia.ufrj.br.

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.

KEYWORDS:

HIV; Ingenol; Latency; NF-kB; P-TEFb; PKC; Resting cells

PMID:
25014309
PMCID:
PMC4383768
DOI:
10.1016/j.virol.2014.05.033
[Indexed for MEDLINE]
Free PMC Article

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