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

Prost, Stéphane; Dantec, Mikael Le; Augé, Sylvie; Grand, Roger Le; Derdouch, Sonia; Aurégan, Gwenaëlle; Déglon, Nicole; Relouzat, Francis; Aubertin, Anne-Marie; Maillère, Bernard; Dusanter‐Fourt, Isabelle; Kirszenbaum, Marek

doi:10.1172/jci33037

Cited by 54 publications

(74 citation statements)

References 61 publications

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“…A role for Nef in impaired hematopoiesis Surprisingly, the Prost study (14) shows that extracellular, soluble forms of the HIV and SIVmac Nef proteins may downmodulate STAT5 expression by activating the transcriptional suppressor PPARγ, thus providing a new mechanism to explain the HIV-associated HSC defects ( Figure 2B). Of note, this inhibitory effect of soluble Nef on the clonogenic potential of progenitor cells (which the authors elegantly map to a central region of HIV-1 Nef between amino acids 66 and 97) might explain why the hematological abnormalities of HIV-infected patients are correlated with disease progression even though HSCs are not directly infected by the virus.…”

Section: Impaired Stat5 and Hsc Function In Siv-infected Macaquesmentioning

confidence: 99%

“…Nef is an early accessory protein of immunodeficiency viruses that is required for efficient viral persistence and strongly accelerates disease progression in HIV-1-infected humans and in experimentally SIV-infected rhesus macaques (18). Nef performs a striking variety of activities that allow the virus to spread effi- (14). In addition, Nef may decrease the production of T cell precursors, thus contributing to the peripheral CD4 + T cell depletion observed in HIV-infected individuals that is caused by both the direct effects of HIV on infected cells and the indirect effects of chronic immune activation.…”

Section: Impaired Stat5 and Hsc Function In Siv-infected Macaquesmentioning

confidence: 99%

“…However, the true in vivo significance of these findings is difficult to assess as the above mentioned results were often obtained using rather artificial experimental conditions characterized by exceptionally high levels of Nef usually produced by bacteria. In this regard, Prost and coworkers (14) demonstrate that sera from SIVmac251-infected macaques can directly suppress STAT5A/B expression and cause HSC dysfunction (and that these effects are reduced by anti-Nef antibodies). These latter results not only support the possibility that the Nef-dependent STAT5A/B suppression occurs at "physiologic" concentrations of this protein, but also raise the question of whether humoral immune responses to Nef, which are detectable in the majority of HIV-1-infected individuals (25), may prevent the development of hematopoietic dysfunction.…”

Section: Impaired Stat5 and Hsc Function In Siv-infected Macaquesmentioning

confidence: 99%

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Is Nef the elusive cause of HIV-associated hematopoietic dysfunction?

Kirchhoff¹,

Silvestri²

2008

J. Clin. Invest.

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Section: Impaired Stat5 and Hsc Function In Siv-infected Macaquesmentioning

confidence: 99%

Section: Impaired Stat5 and Hsc Function In Siv-infected Macaquesmentioning

confidence: 99%

Section: Impaired Stat5 and Hsc Function In Siv-infected Macaquesmentioning

confidence: 99%

See 1 more Smart Citation

Is Nef the elusive cause of HIV-associated hematopoietic dysfunction?

Kirchhoff¹,

Silvestri²

2008

J. Clin. Invest.

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“…The C-terminal His-tagged 210-amino acid HIV-1 Nef proteins (SF2 strain) produced in E. coli were purchased from Jena Bioscience (Jena, Germany). The preparation was shown to be free of endotoxin (,0.03 U/ml), as determined by a Limulus assay (33,34). In selected experiments (Figs.…”

mentioning

confidence: 99%

HIV-1 Proteins Preferentially Activate Anti-Inflammatory M2-Type Macrophages

Chihara

Hashimoto

Osman

et al. 2012

The Journal of Immunology

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HIV-1 proteins, including Tat, gp120, and Nef, activate macrophages (MΦ), which is consistent with the fact that HIV-1 infection is characterized by sustained immune activation. Meanwhile, MΦ are functionally classified into two types: proinflammatory M1-MΦ and anti-inflammatory M2-MΦ. We show that HIV-1 proteins, particularly Nef, preferentially activate M2-MΦ. Extracellular Tat, gp120, and Nef activated MAPK and NF-κB pathways in human peripheral blood monocyte-derived MΦ. However, the activation was marked in M-CSF–derived M2-MΦ but not GM-CSF–derived M1-MΦ. Nef was the most potent activator, and its signaling activation was comparable to that by TNF-α. Indeed, Nef was internalized more rapidly by M2-MΦ than by M1-MΦ. The myristoylation and proline-rich motif of Nef were responsible for the observed signaling activation. Consistent with the activation of MAPK/NF-κB pathways, Nef stimulated the production of a number of proinflammatory cytokines/chemokines by M2-MΦ. However, Nef reduced the expression of CD163 and phagocytosis, the characteristic markers of M2-MΦ, indicating that Nef drives an M2-like to M1-like phenotypic shift. Because the differentiation of most tissue MΦ depends on M-CSF and its receptor, which is the essential axis for the anti-inflammatory M2-MΦ phenotype, the current study reveals an efficient mechanism by which HIV-1 proteins, such as Nef, induce the proinflammatory MΦ.

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“…Eleventh, the male bias in disease worsening in SSc-associated PH (11,12), the lack of sex bias in schistosomiasis-associated PH (13) and the small male bias in development of HIV-associated PH (14) are likely due to localized pulmonary vascular-level activation of immune processes that include STAT5 activation (112)(113)(114)(115)(116)(117).…”

Section: Synthesis Of the Literature On Sex Bias Mediated By The Neurmentioning

confidence: 99%

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

Sehgal

Yang

Miller

2015

Mol Med

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Pulmonary hypertension (PH) is a disease with high morbidity and mortality. The prevalence of idiopathic pulmonary arterial hypertension (IPAH) and hereditary pulmonary arterial hypertension (HPAH) is approximately two-to four-fold higher in women than in men. Paradoxically, there is an opposite male bias in typical rodent models of PH (chronic hypoxia or monocrotaline); in these models, administration of estrogenic compounds (for example, estradiol-17β [E2]) is protective. Further complexities are observed in humans ingesting anorexigens (female bias) and in rodent models, such as after hypoxia plus SU5416/Sugen (little sex bias) or involving serotonin transporter overexpression or dexfenfluramine administration (female bias). These complexities in sex bias in PH remain incompletely understood. We recently discovered that conditional deletion of signal transducer and activator of transcription 5a/b (STAT5a/b) in vascular smooth muscle cells abrogated the male bias in PH in hypoxic mice and that late-stage obliterative lesions in patients of both sexes with IPAH and HPAH showed reduced STAT5a/b, reduced Tyr-P-STAT5 and reduced B-cell lymphoma 6 protein (BCL6). In trying to understand the significance of these observations, we realized that there existed a wellcharacterized E2-sensitive central neuroendocrine mechanism of sex bias, studied over the last 40 years, that, at its peripheral end, culminated in species-specific male ("pulsatile") versus female ("more continuous") temporal patterns of circulating growth hormone (GH) levels leading to male versus female patterned activation of STAT5a/b in peripheral tissues and thus sex-biased expression of hundreds of genes. In this report, we consider the contribution of this neuroendocrine mechanism (hypothalamus-GH-STAT5) in the generation of sex bias in different PH situations.

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

Cited by 54 publications

References 61 publications

Is Nef the elusive cause of HIV-associated hematopoietic dysfunction?

Is Nef the elusive cause of HIV-associated hematopoietic dysfunction?

HIV-1 Proteins Preferentially Activate Anti-Inflammatory M2-Type Macrophages

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

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