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Journal of Virology, September 2002, p. 9407-9419, Vol. 76, No. 18
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.18.9407-9419.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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

Wei Chen,1 Jerrold Sulcove,1 Ian Frank,2 Salman Jaffer,1 Hakan Ozdener,1 and Dennis L. Kolson1*

Departments of Neurology,1 Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 191042

Received 4 March 2002/ Accepted 15 June 2002

Neuronal apoptosis within the central nervous system (CNS) is a characteristic feature of AIDS dementia, and it represents a common mechanism of neuronal death induced by neurotoxins (e.g., glutamate) released from human immunodeficiency virus (HIV)-infected macrophages (HIV/macrophage-induced neurotoxicity). Neuronal apoptosis may result from activation of the intrinsic (mitochondrial/bcl-2 regulated) or extrinsic (death receptor) pathways, although which pathway predominates in CNS HIV infection is unknown. Apoptosis initiated by the intrinsic pathway is typically blocked by antiapoptosis Bcl-2 family proteins, such as Bcl-2 and Bcl-xL, but whether these can block HIV/macrophage-induced neuronal apoptosis is unknown. To determine the potential role of the Bcl-2 family in HIV/macrophage-induced neuronal apoptosis, we developed a unique in vitro model, utilizing the NT2 neuronal cell line, primary astrocytes and macrophages, and primary CNS HIV type 1 (HIV-1) isolates. We validated our model by demonstrating that NT2.N neurons are protected against HIV-infected macrophages by N-methyl-D-aspartate (NMDA) glutamate receptor antagonists, similar to effects seen in primary neurons. We then established stable NT2.N neuronal lines that overexpress Bcl-2 or Bcl-xL (NT2.N/bcl-2 and NT2.N/bcl-xL, respectively) and determined their sensitivity to macrophages infected with primary R5, X4, and R5/X4 HIV-1 isolates. We found that NT2.N/bcl-2 and NT2.N/bcl-xL neurons were resistant to apoptosis induced by either R5, X4, or R5/X4 isolates and that resistance was abrogated by a Bcl-2 antagonist. Thus, the NMDA receptor/bcl-2-regulated apoptotic pathway contributes significantly to HIV/macrophage-induced neuronal apoptosis, and Bcl-2 family proteins protect neurons against the spectrum of primary HIV-1 isolates. Modulation of bcl-2 gene expression may therefore offer adjunctive neuroprotection against development of AIDS dementia.

* Corresponding author. Mailing address: Room 280C, Clinical Research Building, University of Pennsylvania, 415 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 573-3505. Fax: (215) 573-2029. E-mail: kolsond{at}mail.med.upenn.edu.

Journal of Virology, September 2002, p. 9407-9419, Vol. 76, No. 18
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.18.9407-9419.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Hou, W., Wang, X., Ye, L., Zhou, L., Yang, Z.-Q., Riedel, E., Ho, W.-Z. (2009). Lambda Interferon Inhibits Human Immunodeficiency Virus Type 1 Infection of Macrophages. J. Virol. 83: 3834-3842 [Abstract] [Full Text]  
  • O'Donnell, L. A., Agrawal, A., Jordan-Sciutto, K. L., Dichter, M. A., Lynch, D. R., Kolson, D. L. (2006). Human Immunodeficiency Virus (HIV)-Induced Neurotoxicity: Roles for the NMDA Receptor Subtypes. J. Neurosci. 26: 981-990 [Abstract] [Full Text]  


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