Axonal transport of human immunodeficiency virus type 1 envelope protein glycoprotein 120 is found in association with neuronal apoptosis.
Patients infected by human immunodeficiency virus type 1 (HIV-1) develop acquired immune deficiency syndrome-associated dementia complex (ADC), a disorder characterized by a broad spectrum of motor impairments and cognitive deficits. The number of cells in the brain that are productively infected by HIV-1 is relatively small and consists predominantly of macrophages and microglia, yet HIV-1 causes widespread neuronal loss. A better understanding of the pathogenic mechanisms mediating HIV-1 neurotoxicity is crucial for developing effective neuroprotective therapies against ADC. The HIV-1 envelope glycoprotein 120 (gp120), which is shed from the virus, is one of the agents causing neuronal cell death. However, the cellular mechanisms underlying its neurotoxic effect remain unclear. We report that gp120 injected into the rat striatum or hippocampus is sequestered by neurons and subsequently retrogradely transported to distal neurons that project to these brain areas. Cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling, hallmarks of apoptosis, were seen in neurons internalizing and transporting gp120. The retrograde transport of gp120 and apoptosis were mediated by the chemokine receptor CXCR4 because AMD3100, a selective CXCR4 inhibitor, blocked both events. Furthermore, colchicine or nocodazole, two inhibitors of intracellular trafficking, abolished gp120-mediated apoptosis in distal areas. These results indicate that axonal transport of gp120 might play a role in HIV-1-mediated widespread neuronal cell death.
Bachis
Alessia
A
Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
Aden
Sadia A
SA
Nosheny
Rachel L
RL
Andrews
Peter M
PM
Mocchetti
Italo
I
D000818:Animals; D000831:Animals, Newborn; D019380:Anti-HIV Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure / Q000821:virology; D001596:Benzylamines; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D003078:Colchicine / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology; D000080027:Cyclams; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D016253:Microscopy, Immunoelectron / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D015739:Nocodazole / Q000494:pharmacology; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000378:metabolism; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D019380:Anti-HIV Agents; D001596:Benzylamines; C486264:Cxcr4 protein, rat; D000080027:Cyclams; D005904:Glial Fibrillary Acidic Protein; D015699:HIV Envelope Protein gp120; D006571:Heterocyclic Compounds; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D019718:Receptors, CXCR4; D014446:Tyrosine 3-Monooxygenase; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C088327:plerixafor; D015739:Nocodazole; D003078:Colchicine