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The Journal of Neuroscience, June 21, 2006, 26(25):6771-6780; doi:10.1523/JNEUROSCI.1054-06.2006

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Neurobiology of Disease
Axonal Transport of Human Immunodeficiency Virus Type 1 Envelope Protein Glycoprotein 120 Is Found in Association with Neuronal Apoptosis

Alessia Bachis,¹ Sadia A. Aden,¹ Rachel L. Nosheny,¹ Peter M. Andrews,² and Italo Mocchetti¹

Departments of ¹Neuroscience and ²Cell Biology, Georgetown University Medical Center, Washington, DC 20057

Correspondence should be addressed to Dr. Italo Mocchetti, Department of Neuroscience, Georgetown University, Research Building, Room EP04, Box 571464, 3970 Reservoir Road NW, Washington, DC 20057. Email: moccheti{at}georgetown.edu

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.

Key words: basal ganglia; cerebral cortex; CXCR4; hippocampus; neurodegeneration; AIDS dementia complex

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Received Aug. 30, 2005; revised May 10, 2006; accepted May 13, 2006.

Correspondence should be addressed to Dr. Italo Mocchetti, Department of Neuroscience, Georgetown University, Research Building, Room EP04, Box 571464, 3970 Reservoir Road NW, Washington, DC 20057. Email: moccheti{at}georgetown.edu

This article has been cited by other articles:

				H. Kitayama, Y. Miura, Y. Ando, S. Hoshino, Y. Ishizaka, and Y. Koyanagi Human Immunodeficiency Virus Type 1 Vpr Inhibits Axonal Outgrowth through Induction of Mitochondrial Dysfunction J. Virol., March 1, 2008; 82(5): 2528 - 2542. [Abstract] [Full Text] [PDF]

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