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

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. - Highlights: • 3-caproyl-ingenol (ING B) reactivates latent HIV better than SAHA, ingenol 3,20-dibenzoate, TNF-α, PMA and HMBA. • ING B promotes PKC activation and NF-kB translocation to the nucleus. • ING B activates virus transcription of B and non-B subtypes of HIV-1. • INGmore » B activates HIV transcription in infected primary resting CD4+ T cells. • ING B induces higher levels of P-TEFb components in human primary cells.« less
Authors:
 [1] ;  [2] ; ;  [1] ;  [3] ; ; ;  [4] ;  [5] ;  [6] ;  [2] ;  [4] ;  [1] ;  [1]
  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)
Publication Date:
OSTI Identifier:
22435051
Resource Type:
Journal Article
Resource Relation:
Journal Name: Virology; Journal Volume: 462-463; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AIDS VIRUS; CELL NUCLEI; DRUGS; ESTERS; LYMPHOCYTES; PROMOTERS; REGENERATION; TRANSCRIPTION