Titre
Human and simian immunodeficiency viruses deregulate early hematopoiesis through a Nef/PPARgamma/STAT5 signaling pathway in macaques.
Type
article
Institution
Externe
Périodique
Auteur(s)
Prost, S.
Auteure/Auteur
Le Dantec, M.
Auteure/Auteur
Augé, S.
Auteure/Auteur
Le Grand, R.
Auteure/Auteur
Derdouch, S.
Auteure/Auteur
Auregan, G.
Auteure/Auteur
Déglon, N.
Auteure/Auteur
Relouzat, F.
Auteure/Auteur
Aubertin, A.M.
Auteure/Auteur
Maillere, B.
Auteure/Auteur
Dusanter-Fourt, I.
Auteure/Auteur
Kirszenbaum, M.
Auteure/Auteur
Liens vers les personnes
ISSN
0021-9738
Statut éditorial
Publié
Date de publication
2008
Volume
118
Numéro
5
Première page
1765
Dernière page/numéro d’article
1775
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Résumé
Infection of primates by HIV-1 and SIV induces multiple hematological abnormalities of central hematopoietic origin. Although these defects greatly contribute to the pathophysiology of HIV-1 infection, the molecular basis for altered BM function remains unknown. Here we show that when cynomolgus macaques were infected with SIV, the multipotent potential of their hematopoietic progenitor cells was lost, and this correlated with downregulation of STAT5A and STAT5B expression. However, forced expression of STAT5B entirely rescued the multipotent potential of the hematopoietic progenitor cells. In addition, an accessory viral protein required for efficient SIV and HIV replication and pathogenicity, "Negative factor" (Nef), was essential for SIV-mediated impairment of the multipotent potential of hematopoietic progenitors ex vivo and in vivo. This newly uncovered property of Nef was both conserved between HIV-1 and SIV strains and entirely dependent upon the presence of PPARgamma in targeted cells. Further, PPARgamma agonists mimicked Nef activity by inhibiting STAT5A and STAT5B expression and hampering the functionality of hematopoietic progenitors both ex vivo and in vivo. These findings have extended the role of Nef in the pathogenicity of HIV-1 and SIV and reveal a pivotal role for the PPARgamma/STAT5 pathway in the regulation of early hematopoiesis. This study may provide a basis for investigating the potential therapeutic benefits of PPARgamma antagonists in both patients with AIDS and individuals with hematopoietic disorders.
Sujets
PID Serval
serval:BIB_8754B6DFBB02
PMID
Open Access
Oui
Date de création
2011-12-13T15:17:47.048Z
Date de création dans IRIS
2025-05-20T21:29:16Z