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

The Journal of Clinical Investigation
Stéphane ProstMarek Kirszenbaum

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 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 pathog...Continue Reading

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Citations

Jul 14, 2010·The Journal of Infectious Diseases·Bela F AsztalosKeith G Mansfield
Apr 24, 2008·The Journal of Clinical Investigation·Frank Kirchhoff, Guido Silvestri
Nov 26, 2009·Molecular Endocrinology·John P ChuteDonald P McDonnell
May 17, 2011·PloS One·Patricia Ribeiro Dos SantosCécile Butor
May 19, 2010·Cell Host & Microbe·Tamar HermeshCarolina B López
Oct 26, 2010·Biochimica Et Biophysica Acta·G Ferbeyre, R Moriggl
Oct 4, 2016·Frontiers in Immunology·Maria Fernanda PascuttiMartijn A Nolte
Feb 16, 2019·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·Paula Alonso-GuallartRaimon Duran-Struuck
May 10, 2008·Médecine sciences : M/S·Stéphane ProstMarek Kirszenbaum
Aug 28, 2020·Journal of Virology·Angela R Harrison, Gregory W Moseley
Apr 30, 2021·The Journal of Clinical Investigation·Juliette LambertStéphane Prost

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Datasets Mentioned

BETA
DQ267926

Methods Mentioned

BETA
PCR
myristoylation
immunodepletion
density-gradient centrifugation
flow cytometry
immunoprecipitation
transfection

Software Mentioned

NeoMPS
Calc
StatView

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