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Imaging of HIV-1 Envelope-induced Virological Synapse and Signaling on Synthetic Lipid Bilayers
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Role of cholesterol in human immunodeficiency virus type 1 envelope protein-mediated fusion with host cells

Mathias Viard1, Isabella Parolini, Massimo Sargiacomo

  • 1Laboratory of Experimental and Computational Biology, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.

Journal of Virology
|October 22, 2002
PubMed

Insights

Cholesterol depletion and cytoskeletal changes impair HIV-1 Env-mediated fusion in lymphocytes by affecting coreceptor clustering. Restoring cholesterol recovers fusion and chemotaxis, suggesting microvilli

Area of Science:

  • Virology
  • Cell Biology
  • Immunology

Background:

  • Human immunodeficiency virus type 1 (HIV-1) entry into host cells is a complex process involving the viral envelope (Env) protein and host cell receptors.
  • Cholesterol and the actin cytoskeleton play critical roles in cellular membrane dynamics and receptor function, potentially influencing HIV-1 fusion.
  • Understanding the specific roles of cholesterol and cytoskeleton in HIV-1 fusion is crucial for developing targeted antiviral strategies.

Purpose of the Study:

  • To investigate the impact of cholesterol depletion and cytoskeletal alterations on HIV-1 Env-mediated membrane fusion.
  • To determine the role of cholesterol and actin in coreceptor (CXCR4, CCR5) function and HIV-1 entry.
  • To elucidate the mechanisms underlying HIV-1 fusion susceptibility in different cell types.

Main Methods:

  • Dye redistribution assays were used to measure HIV-1 Env-mediated membrane fusion.
  • Peripheral blood lymphocytes (PBL) and human osteosarcoma (HOS) cells were treated with methyl-beta-cyclodextrin (MbetaCD) or cytochalasin to deplete cholesterol or alter the cytoskeleton.
  • Confocal laser scanning microscopy was employed to analyze the colocalization of CD4, CXCR4, and actin.

Main Results:

  • Cholesterol depletion and cytoskeletal changes reduced HIV-1 Env-mediated fusion in PBL, but not in HOS cells with high coreceptor expression.
  • Cholesterol removal inhibited chemotaxis induced by stromal cell-derived factor-1alpha and macrophage inflammatory protein 1beta in both cell types.
  • Fusion and chemotactic activities were restored upon cholesterol repletion in PBL.
  • MbetaCD treatment decreased the colocalization of CD4/CXCR4 with actin in lymphocyte microvilli.

Conclusions:

  • Cholesterol is not essential for HIV-1 Env-mediated fusion itself but is crucial for fusion in cells with low coreceptor density by facilitating coreceptor clustering.
  • Actin polymerization in microvilli likely supports coreceptor clustering required for triggering HIV-1 fusion.
  • These findings highlight the importance of membrane cholesterol and cytoskeletal organization in regulating HIV-1 entry pathways.

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