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HIV-1 gp120 Promotes Lysosomal Exocytosis in Human Schwann Cells.

Frontiers in cellular neuroscience (2019-08-06)
Gaurav Datta, Nicole M Miller, Zahra Afghah, Jonathan D Geiger, Xuesong Chen
ABSTRACT

Human immunodeficiency virus type 1 (HIV-1) associated neuropathy is the most common neurological complication of HIV-1, with debilitating pain affecting the quality of life. HIV-1 gp120 plays an important role in the pathogenesis of HIV neuropathy via direct neurotoxic effects or indirect pro-inflammatory responses. Studies have shown that gp120-induced release of mediators from Schwann cells induce CCR5-dependent DRG neurotoxicity, however, CCR5 antagonists failed to improve pain in HIV- infected individuals. Thus, there is an urgent need for a better understanding of neuropathic pain pathogenesis and developing effective therapeutic strategies. Because lysosomal exocytosis in Schwann cells is an indispensable process for regulating myelination and demyelination, we determined the extent to which gp120 affected lysosomal exocytosis in human Schwann cells. We demonstrated that gp120 promoted the movement of lysosomes toward plasma membranes, induced lysosomal exocytosis, and increased the release of ATP into the extracellular media. Mechanistically, we demonstrated lysosome de-acidification, and activation of P2X4 and VNUT to underlie gp120-induced lysosome exocytosis. Functionally, we demonstrated that gp120-induced lysosome exocytosis and release of ATP from Schwann cells leads to increases in intracellular calcium and generation of cytosolic reactive oxygen species in DRG neurons. Our results suggest that gp120-induced lysosome exocytosis and release of ATP from Schwann cells and DRG neurons contribute to the pathogenesis of HIV-1 associated neuropathy.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-P2X4 Receptor Antibody, Chemicon®, from rabbit
Sigma-Aldrich
Adenosine 5′-triphosphate (ATP) Bioluminescent Assay Kit, for ATP quantitation
Sigma-Aldrich
PKH26 Red Fluorescent Cell Linker Kit for General Cell Membrane Labeling, Distributed for Phanos Technologies
Sigma-Aldrich
Anti-LAMP-1 (CD107a) Antibody, from rabbit, purified by affinity chromatography