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

 Previous Article  |  Next Article 

Journal of Virology, October 1999, p. 8256-8267, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Lymphotropic Virions Affect Chemokine Receptor-Mediated Neural Signaling and Apoptosis: Implications for Human Immunodeficiency Virus Type 1-Associated Dementia

Jialin Zheng,1,2 Anuja Ghorpade,1,2 Douglas Niemann,1,2 Robin L. Cotter,1,2,3 Michael R. Thylin,1,2 Leon Epstein,4 Jennifer M. Swartz,1,2 Robin B. Shepard,1,2 Xiaojuan Liu,1,2 Adeline Nukuna,1,2 and Howard E. Gendelman1,2,3,5,*

Center for Neurovirology and Neurodegenerative Disorders,1 Departments of Pathology and Microbiology2 and Medicine,5 and Eppley Institute for Research in Cancer and Allied Diseases,3 University of Nebraska Medical Center, Omaha, Nebraska 68198-5215, and Department of Neurology, Children's Memorial Hospital, Northwestern University Medical School, Chicago, Illinois 606144

Received 16 December 1998/Accepted 9 July 1999

Chemokine receptors pivotal for human immunodeficiency virus type 1 (HIV-1) infection in lymphocytes and macrophages (CCR3, CCR5, and CXCR4) are expressed on neural cells (microglia, astrocytes, and/or neurons). It is these cells which are damaged during progressive HIV-1 infection of the central nervous system. We theorize that viral coreceptors could effect neural cell damage during HIV-1-associated dementia (HAD) without simultaneously affecting viral replication. To these ends, we studied the ability of diverse viral strains to affect intracellular signaling and apoptosis of neurons, astrocytes, and monocyte-derived macrophages. Inhibition of cyclic AMP, activation of inositol 1,4,5-trisphosphate, and apoptosis were induced by diverse HIV-1 strains, principally in neurons. Virions from T-cell-tropic (T-tropic) strains (MN, IIIB, and Lai) produced the most significant alterations in signaling of neurons and astrocytes. The HIV-1 envelope glycoprotein, gp120, induced markedly less neural damage than purified virions. Macrophage-tropic (M-tropic) strains (ADA, JR-FL, Bal, MS-CSF, and DJV) produced the least neural damage, while 89.6, a dual-tropic HIV-1 strain, elicited intermediate neural cell damage. All T-tropic strain-mediated neuronal impairments were blocked by the CXCR4 antibody, 12G5. In contrast, the M-tropic strains were only partially blocked by 12G5. CXCR4-mediated neuronal apoptosis was confirmed in pure populations of rat cerebellar granule neurons and was blocked by HA1004, an inhibitor of calcium/calmodulin-dependent protein kinase II, protein kinase A, and protein kinase C. Taken together, these results suggest that progeny HIV-1 virions can influence neuronal signal transduction and apoptosis. This process occurs, in part, through CXCR4 and is independent of CD4 binding. T-tropic viruses that traffic in and out of the brain during progressive HIV-1 disease may play an important role in HAD neuropathogenesis.

* Corresponding author. Mailing address: Center for Neurovirology and Neurodegenerative Disorders, 985215 Nebraska Medical Center, Omaha, NE 68198-5215. Phone: (402) 559-8920. Fax: (402) 559-8922. E-mail: hegendel{at}unmc.edu.

Journal of Virology, October 1999, p. 8256-8267, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Gray, L., Roche, M., Churchill, M. J., Sterjovski, J., Ellett, A., Poumbourios, P., Sheffief, S., Wang, B., Saksena, N., Purcell, D. F. J., Wesselingh, S., Cunningham, A. L., Brew, B. J., Gabuzda, D., Gorry, P. R. (2009). Tissue-Specific Sequence Alterations in the Human Immunodeficiency Virus Type 1 Envelope Favoring CCR5 Usage Contribute to Persistence of Dual-Tropic Virus in the Brain. J. Virol. 83: 5430-5441 [Abstract] [Full Text]  
  • Vitvitsky, V., Thomas, M., Ghorpade, A., Gendelman, H. E., Banerjee, R. (2006). A Functional Transsulfuration Pathway in the Brain Links to Glutathione Homeostasis. J. Biol. Chem. 281: 35785-35793 [Abstract] [Full Text]  
  • Huang, M.-B., Jin, L. L., James, C. O., Khan, M., Powell, M. D., Bond, V. C. (2004). Characterization of Nef-CXCR4 Interactions Important for Apoptosis Induction. J. Virol. 78: 11084-11096 [Abstract] [Full Text]  
  • Xu, Y., Kulkosky, J., Acheampong, E., Nunnari, G., Sullivan, J., Pomerantz, R. J. (2004). HIV-1-mediated apoptosis of neuronal cells: Proximal molecular mechanisms of HIV-1-induced encephalopathy. Proc. Natl. Acad. Sci. USA 101: 7070-7075 [Abstract] [Full Text]  
  • James, C. O., Huang, M.-B., Khan, M., Garcia-Barrio, M., Powell, M. D., Bond, V. C. (2004). Extracellular Nef Protein Targets CD4+ T Cells for Apoptosis by Interacting with CXCR4 Surface Receptors. J. Virol. 78: 3099-3109 [Abstract] [Full Text]  
  • Persidsky, Y., Gendelman, H. E. (2003). Mononuclear phagocyte immunity and the neuropathogenesis of HIV-1 infection. J. Leukoc. Biol. 74: 691-701 [Abstract] [Full Text]  
  • Bachis, A., Major, E. O., Mocchetti, I. (2003). Brain-Derived Neurotrophic Factor Inhibits Human Immunodeficiency Virus-1/gp120-Mediated Cerebellar Granule Cell Death by Preventing gp120 Internalization. J. Neurosci. 23: 5715-5722 [Abstract] [Full Text]  
  • Chen, W., Sulcove, J., Frank, I., Jaffer, S., Ozdener, H., Kolson, D. L. (2002). Development of a Human Neuronal Cell Model for Human Immunodeficiency Virus (HIV)-Infected Macrophage-Induced Neurotoxicity: Apoptosis Induced by HIV Type 1 Primary Isolates and Evidence for Involvement of the Bcl-2/Bcl-xL-Sensitive Intrinsic Apoptosis Pathway. J. Virol. 76: 9407-9419 [Abstract] [Full Text]  
  • Gorry, P. R., Taylor, J., Holm, G. H., Mehle, A., Morgan, T., Cayabyab, M., Farzan, M., Wang, H., Bell, J. E., Kunstman, K., Moore, J. P., Wolinsky, S. M., Gabuzda, D. (2002). Increased CCR5 Affinity and Reduced CCR5/CD4 Dependence of a Neurovirulent Primary Human Immunodeficiency Virus Type 1 Isolate. J. Virol. 76: 6277-6292 [Abstract] [Full Text]  
  • Tanaka, R., Yoshida, A., Murakami, T., Baba, E., Lichtenfeld, J., Omori, T., Kimura, T., Tsurutani, N., Fujii, N., Wang, Z.-X., Peiper, S. C., Yamamoto, N., Tanaka, Y. (2001). Unique Monoclonal Antibody Recognizing the Third Extracellular Loop of CXCR4 Induces Lymphocyte Agglutination and Enhances Human Immunodeficiency Virus Type 1-Mediated Syncytium Formation and Productive Infection. J. Virol. 75: 11534-11543 [Abstract] [Full Text]  
  • Choe, W., Volsky, D. J., Potash, M. J. (2001). Induction of Rapid and Extensive beta -Chemokine Synthesis in Macrophages by Human Immunodeficiency Virus Type 1 and gp120, Independently of Their Coreceptor Phenotype. J. Virol. 75: 10738-10745 [Abstract] [Full Text]  
  • Gorry, P. R., Bristol, G., Zack, J. A., Ritola, K., Swanstrom, R., Birch, C. J., Bell, J. E., Bannert, N., Crawford, K., Wang, H., Schols, D., De Clercq, E., Kunstman, K., Wolinsky, S. M., Gabuzda, D. (2001). Macrophage Tropism of Human Immunodeficiency Virus Type 1 Isolates from Brain and Lymphoid Tissues Predicts Neurotropism Independent of Coreceptor Specificity. J. Virol. 75: 10073-10089 [Abstract] [Full Text]  
  • Canki, M., Thai, J. N. F., Chao, W., Ghorpade, A., Potash, M. J., Volsky, D. J. (2001). Highly Productive Infection with Pseudotyped Human Immunodeficiency Virus Type 1 (HIV-1) Indicates No Intracellular Restrictions to HIV-1 Replication in Primary Human Astrocytes. J. Virol. 75: 7925-7933 [Abstract] [Full Text]  
  • Persidsky, Y., Zheng, J., Miller, D., Gendelman, H. E. (2000). Mononuclear phagocytes mediate blood-brain barrier compromise and neuronal injury during HIV-1-associated dementia. J. Leukoc. Biol. 68: 413-422 [Abstract] [Full Text]  
  • Johnston, J. B., Jiang, Y., van Marle, G., Mayne, M. B., Ni, W., Holden, J., McArthur, J. C., Power, C. (2000). Lentivirus Infection in the Brain Induces Matrix Metalloproteinase Expression: Role of Envelope Diversity. J. Virol. 74: 7211-7220 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»