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Journal of Virology, July 2001, p. 6572-6583, Vol. 75, No. 14
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.14.6572-6583.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Mononuclear Phagocyte Differentiation, Activation, and Viral Infection Regulate Matrix Metalloproteinase Expression: Implications for Human Immunodeficiency Virus Type 1-Associated Dementia

Anuja Ghorpade,1,* Raisa Persidskaia,1 Radhika Suryadevara,1 Myhanh Che,1 Xiao Juan Liu,2 Yuri Persidsky,1 and Howard E. Gendelman3

The Center for Neurovirology and Neurodegenerative Disorders, Department of Pathology and Microbiology,1 and Departments of Internal Medicine3 and Oral Biology,2 Nebraska Medical Center, Omaha, Nebraska 68198-5215

Received 1 November 2000/Accepted 19 April 2001

The pathogenesis of human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD) is mediated mainly by mononuclear phagocyte (MP) secretory products and their interactions with neural cells. Viral infection and MP immune activation may affect leukocyte entry into the brain. One factor that influences central nervous system (CNS) monocyte migration is matrix metalloproteinases (MMPs). In the CNS, MMPs are synthesized by resident glial cells and affect the integrity of the neuropil extracellular matrix (ECM). To ascertain how MMPs influence HAD pathogenesis, we studied their secretion following MP differentiation, viral infection, and cellular activation. HIV-1-infected and/or immune-activated monocyte-derived macrophages (MDM) and human fetal microglia were examined for production of MMP-1, -2, -3, and -9. MMP expression increased significantly with MP differentiation. Microglia secreted high levels of MMPs de novo that were further elevated following CD40 ligand-mediated cell activation. Surprisingly, HIV-1 infection of MDM led to the down-regulation of MMP-9. In encephalitic brain tissue, MMPs were expressed within perivascular and parenchymal MP, multinucleated giant cells, and microglial nodules. These data suggest that MMP production in MP is dependent on cell type, differentiation, activation, and/or viral infection. Regulation of MMP expression by these factors may contribute to neuropil ECM degradation and leukocyte migration during HAD.

* The Center for Neurovirology and Neurodegenerative Disorders, Departments of Pathology and Microbiology, 985215 Nebraska Medical Center, Omaha, NE 68198-5215. Phone: (402) 559-5275. Fax: (402) 559-8922. E-mail: aghorpad{at}unmc.edu.

Journal of Virology, July 2001, p. 6572-6583, Vol. 75, No. 14
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.14.6572-6583.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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