GM-CSF and M-CSF modulate beta-chemokine and HIV-1 expression in microglia
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Published on: August 11, 2023
Qiusheng Si1, Melissa Cosenza, Meng-Liang Zhao
1Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Abstract:
Significant numbers of patients with acquired immunodeficiency syndrome (AIDS) develop CNS infection primarily in macrophages and microglial cells. Therefore, the regulation of human immunodeficiency virus type 1 (HIV-1) infection and activation of the brain mononuclear phagocytes subsequent to infection are important areas of investigation. In the current report, we studied the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage-CSF (M-CSF) in the expression of antiviral beta-chemokines and HIV-1 p24 in cultures of primary human fetal microglia. We found that stimulation with GM-CSF or M-CSF induced macrophage inflammatory proteins (MIP-1alpha and MIP-1beta) and augmented RANTES expression, after HIV-1 infection of microglia. This was not due to the effect of GM-CSF on viral expression because GM-CSF was neither necessary nor stimulatory for viral infection, nor did GM-CSF enhance the expression of env-pseudotyped reporter viruses. Blocking GM-CSF-induced microglial proliferation by nocodazole had no effect on beta-chemokine or p24 expression. The functional significance of the GM-CSF-induced beta-chemokines was suggested by the finding that, in the presence of GM-CSF, exogenous beta-chemokines lost their anti-HIV-1 effects. We further show that although HIV-1-infected microglia produced M-CSF, they failed to produce GM-CSF. In vivo, GM-CSF expression was localized to activated astrocytes and some inflammatory cells in HIV-1 encephalitis, suggesting paracrine activation of microglia through GM-CSF. Our results demonstrate a complex interplay between CSFs, chemokines, and virus in microglial cells and may have bearing on the interpretation of data derived in vivo and in vitro.
Insights
Granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage-CSF (M-CSF) influence antiviral responses in HIV-1 infected brain cells. These factors impact chemokine expression, potentially altering HIV-1
Area of Science:
- Neuroimmunology
- Virology
- Cellular Biology
Background:
- Acquired immunodeficiency syndrome (AIDS) frequently involves central nervous system (CNS) infections, particularly within macrophages and microglial cells.
- Understanding the regulation of human immunodeficiency virus type 1 (HIV-1) infection and the activation of brain mononuclear phagocytes is crucial.
Purpose of the Study:
- To investigate the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage-colony stimulating factor (M-CSF) in the expression of antiviral beta-chemokines and HIV-1 p24.
- To elucidate the complex interplay between colony-stimulating factors (CSFs), chemokines, and HIV-1 within microglial cells.
Main Methods:
- Primary human fetal microglia cultures were used to study the effects of GM-CSF and M-CSF on HIV-1 infection.
- Expression of HIV-1 p24 and beta-chemokines (MIP-1alpha, MIP-1beta, RANTES) was measured following stimulation with CSFs.
- The impact of GM-CSF on viral replication and microglial proliferation was assessed. In vivo studies examined GM-CSF expression in HIV-1 encephalitis.
Main Results:
- GM-CSF and M-CSF stimulation induced macrophage inflammatory proteins (MIP-1alpha and MIP-1beta) and augmented RANTES expression in HIV-1 infected microglia.
- GM-CSF was not essential for or stimulatory to HIV-1 infection in microglia.
- GM-CSF stimulation rendered exogenous beta-chemokines less effective against HIV-1, and in vivo, GM-CSF was found in activated astrocytes and inflammatory cells during HIV-1 encephalitis.
Conclusions:
- GM-CSF and M-CSF play a significant role in modulating antiviral beta-chemokine expression in HIV-1 infected microglia.
- The findings suggest a complex paracrine activation mechanism of microglia by GM-CSF in CNS HIV-1 infection.
- This research provides insights into the in vivo and in vitro dynamics of HIV-1 infection within the brain's immune cells.
