CXCR3 activation by lentivirus infection suppresses neuronal autophagy: neuroprotective effects of antiretroviral therapy.
Previous studies have implicated CXCL12 in the neuropathogenesis of HIV infection. Proteolysis of CXCL12 generates a neurotoxic molecule, CXCL12(5-67), which engages and activates CXCR3, in addition to exhibiting increased expression in the brains of patients with HIV-associated dementia (HAD). Herein, we investigated CXCR3-mediated neuronal injury, particularly, its contribution to autophagy suppression and the concomitant effects of antiretroviral therapy using human brain samples and models of HIV neuropathogenesis. Neurons in the brains of HAD patients and feline immunodeficiency virus (FIV)-infected animals, as well as cultured human neurons, expressed CXCR3, which was modulated in a ligand-specific manner. Exposure of human neurons to CXCL12(5-67) caused a reduction in the autophagy-associated molecule LC3 (P<0.05) and neuronal survival (P<0.05), which recapitulated findings in FIV- and HIV-infected brains (P<0.05). Oral didanosine (ddI) treatment of FIV-infected animals reduced neurobehavioral abnormalities in conjunction with diminished plasma viral load (P<0.05). F4/80 transcript abundance and CXCL12(5-67) immunoreactivity were reduced with restored neuronal LC3 expression in the brains of FIV-infected animals after ddI treatment (P<0.05). ddI treatment also prevented microglial activation and depletion of synaptic proteins in the cortex of FIV-infected animals (P<0.05). These findings indicate that the beneficial effects of ddI might be a consequence of a reduced systemic viral burden and concurrent leukocyte activation, leading to diminished neuroinflammation with preservation of neuronal autophagy by regulating CXCR3 activation.
Zhu
Yu
Y
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Vergote
David
D
Pardo
Carlos
C
Noorbakhsh
Farshid
F
McArthur
Justin C
JC
Hollenberg
Morley D
MD
Overall
Christopher M
CM
Power
Christopher
C
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D001343:Autophagy; D001921:Brain / Q000473:pathology / Q000821:virology; D002415:Cats; D016049:Didanosine / Q000494:pharmacology* / Q000627:therapeutic use; D016181:Feline Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000473:pathology; D015658:HIV Infections / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D016180:Lentivirus Infections / Q000188:drug therapy* / Q000473:pathology; D009474:Neurons / Q000473:pathology / Q000821:virology*; D018696:Neuroprotective Agents; D054367:Receptors, CXCR3 / Q000378:metabolism* / Q000502:physiology
D019380:Anti-HIV Agents; C515187:CXCR3 protein, human; D018696:Neuroprotective Agents; D054367:Receptors, CXCR3; D016049:Didanosine