This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, K. Articles by Power, C. Search for Related Content PubMed PubMed Citation Articles by Zhang, K. Articles by Power, C.

Human Immunodeficiency Virus Type 1 Envelope-Mediated Neuronal Death: Uncoupling of Viral Replication and Neurotoxicity

Departments of Clinical Neurosciences,¹ Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada,² University of Nairobi, Nairobi, Kenya,³ Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, Montana⁴

Received 14 January 2003/ Accepted 25 March 2003

Although brain tissue from patients with human immunodeficiency virus (HIV) and/or AIDS is consistently infected by HIV type 1 (HIV-1), only 20 to 30% of patients exhibit clinical or neuropathological evidence of brain injury. Extensive HIV-1 sequence diversity is present in the brain, which may account in part for the variability in the occurrence of HIV-induced brain disease. Neurological injury caused by HIV-1 is mediated directly by neurotoxic viral proteins or indirectly through excess production of host molecules by infected or activated glial cells. To elucidate the relationship between HIV-1 infection and neuronal death, we examined the neurotoxic effects of supernatants from human 293T cells or macrophages expressing recombinant HIV-1 virions or gp120 proteins containing the V1V3 or C2V3 envelope region from non-clade B, brain-derived HIV-1 sequences. Neurotoxicity was measured separately as apoptosis or total neuronal death, with apoptosis representing 30 to 80% of the total neuron death observed, depending on the individual virus. In addition, neurotoxicity was dependent on expression of HIV-1 gp120 and could be blocked by anti-gp120 antibodies, as well as by antibodies to the human CCR5 and CXCR4 chemokine receptors. Despite extensive sequence diversity in the recombinant envelope region (V1V3 or C2V3), there was limited variation in the neurotoxicity induced by supernatants from transfected 293T cells. Conversely, supernatants from infected macrophages caused a broader range of neurotoxicity levels that depended on each virus and was independent of the replicative ability of the virus. These findings underscore the importance of HIV-1 envelope protein expression in neurotoxic pathways associated with HIV-induced brain disease and highlight the envelope as a target for neuroprotective therapeutic interventions.

This article has been cited by other articles:

• Muratori, C., Sistigu, A., Ruggiero, E., Falchi, M., Bacigalupo, I., Palladino, C., Toschi, E., Federico, M. (2007). Macrophages Transmit Human Immunodeficiency Virus Type 1 Products to CD4-Negative Cells: Involvement of Matrix Metalloproteinase 9. J. Virol. 81: 9078-9087 [Abstract] [Full Text]  
• Antony, J. M., Ellestad, K. K., Hammond, R., Imaizumi, K., Mallet, F., Warren, K. G., Power, C. (2007). The Human Endogenous Retrovirus Envelope Glycoprotein, Syncytin-1, Regulates Neuroinflammation and Its Receptor Expression in Multiple Sclerosis: A Role for Endoplasmic Reticulum Chaperones in Astrocytes. J. Immunol. 179: 1210-1224 [Abstract] [Full Text]  
• Jones, G. J., Barsby, N. L., Cohen, E. A., Holden, J., Harris, K., Dickie, P., Jhamandas, J., Power, C. (2007). HIV-1 Vpr Causes Neuronal Apoptosis and In Vivo Neurodegeneration. J. Neurosci. 27: 3703-3711 [Abstract] [Full Text]  
• Marozsan, A. J., Moore, D. M., Lobritz, M. A., Fraundorf, E., Abraha, A., Reeves, J. D., Arts, E. J. (2005). Differences in the Fitness of Two Diverse Wild-Type Human Immunodeficiency Virus Type 1 Isolates Are Related to the Efficiency of Cell Binding and Entry. J. Virol. 79: 7121-7134 [Abstract] [Full Text]  
• Strain, M. C., Letendre, S., Pillai, S. K., Russell, T., Ignacio, C. C., Gunthard, H. F., Good, B., Smith, D. M., Wolinsky, S. M., Furtado, M., Marquie-Beck, J., Durelle, J., Grant, I., Richman, D. D., Marcotte, T., McCutchan, J. A., Ellis, R. J., Wong, J. K. (2005). Genetic Composition of Human Immunodeficiency Virus Type 1 in Cerebrospinal Fluid and Blood without Treatment and during Failing Antiretroviral Therapy. J. Virol. 79: 1772-1788 [Abstract] [Full Text]  
• Jian, H., Zhao, L.-J. (2003). Pro-apoptotic Activity of HIV-1 Auxiliary Regulatory Protein Vpr Is Subtype-dependent and Potently Enhanced by Nonconservative Changes of the Leucine Residue at Position 64. J. Biol. Chem. 278: 44326-44330 [Abstract] [Full Text]