Schwann cell chemokine receptors mediate HIV-1 gp120 toxicity to sensory neurons.
Human immunodeficiency virus (HIV)-associated sensory neuropathy (HIV-SN) is the most common neurological complication of HIV infection. Currently, the pathogenesis of HIV-SN is unknown. Because there is no convincing evidence of neuronal infection, HIV neurotoxicity is likely to be effected either by secreted viral proteins such as the envelope glycoprotein gp120 or by neurotoxic cytokines released from infected/activated glial cells. We describe a model of gp120 toxicity to primary sensory neurons, in which gp120 induces neuritic degeneration and neuronal apoptosis. We show that Schwann cells, the cells that ensheath peripheral nerve axons, and which traditionally have been viewed as having a passive, supporting role, mediate this neurotoxicity. Ligation of the chemokine receptor CXCR4 on Schwann cells by gp120 resulted in the release of RANTES, which induced dorsal root ganglion neurons to produce tumor necrosis factor-alpha and subsequent TNFR1-mediated neurotoxicity in an autocrine fashion. This newly described Schwann cell-neuron interaction may be pathogenically relevant not only in HIV-SN but also in other peripheral neuropathies.
Keswani
Sanjay C
SC
Department of Neurology, The Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287, USA.
Polley
Michelle
M
Pardo
Carlos A
CA
Griffin
John W
JW
McArthur
Justin C
JC
Hoke
Ahmet
A
D000818:Animals; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000096:biosynthesis; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D003574:Cytochrome c Group / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005727:Ganglia, Spinal / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D015497:HIV-1; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D023421:Models, Animal; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009475:Neurons, Afferent / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010523:Peripheral Nervous System Diseases / Q000821:virology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012583:Schwann Cells / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C515255:CXCL12 protein, human; D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D003574:Cytochrome c Group; D015699:HIV Envelope Protein gp120; D019718:Receptors, CXCR4; D014409:Tumor Necrosis Factor-alpha