Mononuclear phagocyte differentiation, activation, and viral infection regulate matrix metalloproteinase expression: Implications for human immunodeficiency virus type 1-associated dementia

The pathogenesis of human immunodeficiency virus type 1 (HIV-l)-associated dementia (HAD) is mediated mainly by mononuclear phagocyte (MP) secretory p roducts and their interactions with neural cells, Viral infection and R;IP immune activation may affect leukocyte entry into the brain. One factor tha t influences central nervous system (CNS) monocyte migration is matrix meta lloproteinases (MMPs). In the CNS, MMPs are synthesized by resident glial c ells and affect the integrity of the neuropil extracellular matrix (ECM). T o ascertain how MMPs influence HAD pathogenesis, we studied their secretion following MP differentiation, viral infection, and cellular activation. HI V-l-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 wer e expressed within perivascular and parenchymal MP, multinucleated giant ce lls, and microglial nodules. These data suggest that MMP production in MP i s dependent on cell type, differentiation, activation, and/or viral infecti on. Regulation of MMP expression by these factors may contribute to neuropi l ECM degradation and leukocyte migration during HAD.