Human and simian immunodeficiency viruses deregulate early hematopoiesis through a Nef/PPARγ/STAT5 signaling pathway in macaques
Stéphane Prost, … , Isabelle Dusanter-Fourt, Marek Kirszenbaum
Stéphane Prost, … , Isabelle Dusanter-Fourt, Marek Kirszenbaum
Published April 22, 2008
Citation Information: J Clin Invest. 2008;118(5):1765-1775. https://doi.org/10.1172/JCI33037.
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Research Article

Human and simian immunodeficiency viruses deregulate early hematopoiesis through a Nef/PPARγ/STAT5 signaling pathway in macaques

Abstract

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 PPARγ in targeted cells. Further, PPARγ 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 PPARγ/STAT5 pathway in the regulation of early hematopoiesis. This study may provide a basis for investigating the potential therapeutic benefits of PPARγ antagonists in both patients with AIDS and individuals with hematopoietic disorders.

Authors

Stéphane Prost, Mikael Le Dantec, Sylvie Augé, Roger Le Grand, Sonia Derdouch, Gwenaelle Auregan, Nicole Déglon, Francis Relouzat, Anne-Marie Aubertin, Bernard Maillere, Isabelle Dusanter-Fourt, Marek Kirszenbaum

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Figure 2

Nef mimics SIV actions on hematopoietic progenitors.

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Nef mimics SIV actions on hematopoietic progenitors. (A–C) CFC assays we...
(A–C) CFC assays were performed with CD34+ cells isolated from 3–4 control animals following incubation for 48 hours with (A) plasma from noninfected animals in the absence (control) or presence of infectious or heat-inactivated SIVmac251 particles (1 × 102 particles/ml), (B) plasma from noninfected animal (control) or plasma from 4 chronically infected macaques without (–) or with (+) Nef immunodepletion, or (C) with various concentrations of recombinant SIVmac251 Nef. (D) CFC assays were performed with CD34+ BM cells isolated from SIVmac251-infected or noninfected macaques. Progenitors from uninfected animals were either left untreated or incubated for 48 hours with the viral isolate SIVmac251, molecular clones BK28-41 (BK) or BK28-41ΔNef (BKΔ) (1 × 102 infectious particles/ml), or with rNef (0.15 μM) before being processed for CFC assays. (E) Inhibitory activity of recombinant myristoylated HIV-1 Nef was assayed on CD34+ BM cells isolated from 2 healthy macaques. CD34+ BM cells were preincubated for 48 hours with the indicated concentration of myristoylated HIV-1 Nef before CFC assays. Horizontal lines and the diagonal line in C indicate mean of CFC numbers scored from all cell cultures from the animals analyzed. Each kind of symbol represents samples from a single animal.