A new study in the free access Journal of Clinical Investigation makes a compelling case that the HIV protein Nef is responsible for the hematopoietic abnormalities (anemia, granulocytopenia, and thrombocytopenia) that have been reported in people with HIV infection. Researchers led by Stéphane Prost report that Nef interacts with a nuclear receptor called PPARγ, causing suppression of two signaling proteins, STAT5A and STAT5B, known to be important for the development of hematopoietic stem cells (HSCs). The study used multiple different approaches to verify that a specific region of the nef gene which is conserved among different HIV-1 and SIV strains triggered HSC dysfunction. The authors conclude by suggesting that the study “provides new clues for the development of novel drugs targeting PPARγ activity to cure hematopoietic disorders, including those affecting seropositive/AIDS patients.”
In an accompanying commentary, Frank Kirchhoff and Guido Silvestri praise the work but also caution that “much work will be required to define the mechanism by which extracellular Nef induces PPARγ and to determine whether the levels of Nef in blood and bone marrow are sufficient to impair HSC function during HIV infection.” They also note that “as STAT5 signaling plays a critical role in T cell development and function, an additional question is whether Nef also affects T cell homeostasis by suppressing STAT5A/B function in other, more mature T cell subsets.”
J. Clin. Invest. - (2008). doi:10.1172/JCI35487.
Commentary
Is Nef the elusive cause of HIV-associated hematopoietic dysfunction?
Frank Kirchhoff1 and Guido Silvestri2
1Institute of Virology, University of Ulm, Ulm, Germany.
2Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
HIV-associated hematological abnormalities involve all lineages of blood cells, thus implying that the virus impairs the function of early HSCs. However, the underlying mechanisms of this defect are unknown, particularly since HSCs are largely resistant to HIV-1 infection. In this issue of the JCI, Prost and colleagues show that the viral accessory protein Negative factor (Nef) plays a potentially critical role in the pathogenesis of HIV/SIV-associated hematopoietic dysfunction by affecting the clonogenic potential of HSCs. Soluble Nef induces PPARγ in uninfected HSCs, thereby suppressing the expression of STAT5A and STAT5B, two factors necessary for proper HSC function. The identification of this novel activity of extracellular Nef defines a new mechanism of HIV/SIV pathogenesis and suggests that approaches aimed at increasing STAT5A and STAT5B expression may be considered in HIV-infected individuals with prominent hematological abnormalities. The results also raise the question of whether dysregulation of hematopoiesis by extracellular Nef plays a role in the development of T cell immunodeficiency and the high levels of chronic immune activation associated with AIDS.
J. Clin. Invest. doi:10.1172/JCI33037.
Research Article
Stéphane Prost1,2,3, Mikael Le Dantec1, Sylvie Augé4,5, Roger Le Grand1, Sonia Derdouch1, Gwenaelle Auregan1,6, Nicole Déglon6, Francis Relouzat2,3, Anne-Marie Aubertin7, Bernard Maillere8, Isabelle Dusanter-Fourt4,5 and Marek Kirszenbaum1
1Immunovirology Division and
2Innovative Therapy Division, Institute of Emerging Diseases and Innovative Therapies, CEA, Fontenay-aux-Roses, France.
3INSERM-CEA-Paris XI, UMR U733, CEA, Fontenay-aux-Roses, France.
4Institut Cochin, Université Paris Descartes, CNRS (UMR8104), Paris, France.
5INSERM U567, Paris, France.
6CEA, I2BM et programme MIRCen, Orsay, France.
7Laboratoire de Virologie, Université Louis Pasteur, Strasbourg, France.
8CEA, IBITEC-S, Service d’Ingénierie Moleculaire des Protéines, Saclay, France.
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.
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