Reactivation of latent HIV-1 in vitro using an ethanolic extract from Euphorbia umbellata (Euphorbiaceae) latex.

Ana Luiza Chaves Valadão,Barbara Simonson Gonçalves,Viviane A Oliveira Silva,Antonio Carlos Siani,Gabriel Gonçalves,Átila Duque Rossi,Cleonice Alves De Melo Bento,Renato Santana Aguiar,Marcelo Trovó,João Batista De Freitas Tostes,Rui Manuel Reis,Amilcar Tanuri,Paulo Damasco,Rodrigo Delvecchio Da Cunha,Paula Pezzuto

doi:10.1371/journal.pone.0207664

Abstract

Euphorbia umbellata (E. umbellata) belongs to Euphorbiaceae family, popularly known as Janauba, and its latex contains a combination of phorbol esters with biological activities described to different cellular protein kinase C (PKC) isoforms. Here, we identified deoxi-phorbol esters present in E. umbellata latex alcoholic extract that are able to increase HIV transcription and reactivate virus from latency models. This activity is probably mediated by NF-kB activation followed by nuclear translocation and binding to the HIV LTR promoter. In addition, E. umbellata latex extract induced the production of pro inflammatory cytokines in vitro in human PBMC cultures. This latex extract also activates latent virus in human PBMCs isolated from HIV positive patients as well as latent SIV in non-human primate primary CD4+ T lymphocytes. Together, these results indicate that the phorbol esters present in E. umbellata latex are promising candidate compounds for future clinical trials for shock and kill therapies to promote HIV cure and eradication.

Highlights

The Acquired Immunodeficiency Syndrome (AIDS) is caused by the Human Immunodeficiency Virus (HIV), which was identified in 1983 [1,2]
In this work we evaluated the ability of an ethanolic extract obtained from Janauba latex (JALEx) to reactivate latent HIV-1 and investigated the molecular mechanisms involved in this activity
In order to analyze the ability of JALEx to regulate different T cell phenotypes in the context of HIV-1 infection, samples of the peripheral blood of 15 adults Antiretroviral Therapy (ART)-treated patients (8 women and 9 men), with a mean plasma viral load of 953 ± 1.924 copies of RNA/mL and CD4+ (845 ± 345/mm3) and CD8+ (845 ± 345/mm3) higher than 350 cells/mm3, were collected and peripheral blood mononuclear cells (PBMCs) were obtained from Ficoll-Paque gradient

Summary

Introduction

The Acquired Immunodeficiency Syndrome (AIDS) is caused by the Human Immunodeficiency Virus (HIV), which was identified in 1983 [1,2]. In the context of HIV-1 reactivation, HDAC inhibitors promote transcription of the HIV-1 long terminal repeat (LTR) [10,11,12,13] This strategy is called “shock and kill” and it postulates that memory CD4+ T lymphocytes treated with LRA along with ART could purge totally or partially the viral reservoirs while blocking replication of emergent latent virus, leading to a HIV eradication or at least a functional cure [14]. Another promising class of molecules with therapeutic potential as possible candidates for reactivation of viral reservoirs are the Protein Kinase C (PKC) agonists [7]. All these properties make JALEx a promising natural medicine to be used in HIV cure strategies

Material and methods

Ethic statement

Results

Discussion