title: Reactivation of latent HIV-1 by new semi-synthetic ingenol esters.
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.
authors.affiliation: Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Diego
authors.initials: D
authors.lastname: Pandeló José
authors.affiliation: Department of Medicine, Microbiology and Immunology, University of California at San Francisco, San Francisco, CA 94143-0703, United States.
authors.forename: Koen
authors.initials: K
authors.lastname: Bartholomeeusen
authors.affiliation: Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Rodrigo Delvecchio
authors.initials: RD
authors.lastname: da Cunha
authors.affiliation: Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Celina Monteiro
authors.initials: CM
authors.lastname: Abreu
authors.affiliation: PlantaAnalytica LLC, Danbury, CT 06810, United States.
authors.forename: Jan
authors.initials: J
authors.lastname: Glinski
authors.affiliation: Kyolab Laboratories, Valinhos, São Paulo 13273-105, Brazil.
authors.forename: Thais Barbizan Ferreira
authors.initials: TB
authors.lastname: da Costa
authors.affiliation: Kyolab Laboratories, Valinhos, São Paulo 13273-105, Brazil.
authors.forename: Ana Flávia Mello
authors.initials: AF
authors.lastname: Bacchi Rabay
authors.affiliation: Kyolab Laboratories, Valinhos, São Paulo 13273-105, Brazil.
authors.forename: Luiz Francisco
authors.initials: LF
authors.lastname: Pianowski Filho
authors.affiliation: Lex Company Research Laboratories, Shirley 01464, MA, United States.
authors.forename: Lech W
authors.initials: LW
authors.lastname: Dudycz
authors.affiliation: Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru 560064, India.
authors.forename: Udaykumar
authors.initials: U
authors.lastname: Ranga
authors.affiliation: Department of Medicine, Microbiology and Immunology, University of California at San Francisco, San Francisco, CA 94143-0703, United States.
authors.forename: Boris Matija
authors.initials: BM
authors.lastname: Peterlin
authors.affiliation: Kyolab Laboratories, Valinhos, São Paulo 13273-105, Brazil.
authors.forename: Luiz Francisco
authors.initials: LF
authors.lastname: Pianowski
authors.affiliation: Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Amilcar
authors.initials: A
authors.lastname: Tanuri
authors.affiliation: Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil. Electronic address: santana@biologia.ufrj.br.
authors.forename: Renato Santana
authors.initials: RS
authors.lastname: Aguiar
mesh_terms: D002460:Cell Line; D004224:Diterpenes / Q000378:metabolism*; D004952:Esters / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D004224:Diterpenes; D004952:Esters; C008125:ingenol
keywords: HIV; Ingenol; Latency; NF-kB; P-TEFb; PKC; Resting cells