Interferon-gamma inhibits HIV-induced invasiveness of monocytes.
HIV-infected monocytes form highly invasive network on basement membrane matrix and secrete high levels of 92-kd metalloproteinase (MMP-9), an enzyme that degrades basement membrane proteins. In the present study, using matrigel as a model basement membrane system, we demonstrate that treatment of human immunodeficiency virus (HIV)-infected monocytes with interferon-gamma at 50 U/ml inhibited the ability of infected monocytes to form an invasive network on matrigel and their invasion through the matrigel matrix. These effects were associated with a significant reduction in the levels of MMP-9 produced by HIV-infected monocytes treated with interferon-gamma 1 day prior to infection with HIV as compared with that of untreated HIV-infected monocytes. Monocytes treated with interferon-gamma 1 day after HIV infection showed the presence of integrated HIV sequences; however, the levels of MMP-9 were substantially lower than those produced by monocytes inoculated with live HIV, heat-inactivated HIV, or even the control uninfected monocytes. Exposure of monocytes to heat-inactivated HIV did not result in increased invasiveness or high MMP-9 production, suggesting that regulation of metalloproteinase by monocytes was independent of CD4-gp120 interactions and required active virus infection. Furthermore, addition of interferon-gamma to monocytes on day 10 after infection inhibited MMP-9 production by more than threefold with no significant reduction of virus replication. These results indicate that the mechanism of interferon-gamma-induced down-regulation of MMP-9 levels and reduced monocyte invasiveness may be mediated by a mechanism independent of antiviral activity of IFN-gamma in monocytes. Down-regulation of MMP-9 in HIV-infected monocytes by interferon-gamma may play an important role in the control of HIV pathogenesis.
D000998:Antiviral Agents / Q000494:pharmacology*; D001485:Basement Membrane / Q000473:pathology; D002478:Cells, Cultured; D017364:Collagenases / Q000096:biosynthesis; D006678:HIV / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9; D009000:Monocytes / Q000187:drug effects* / Q000473:pathology / Q000821:virology
D000998:Antiviral Agents; D007371:Interferon-gamma; D017364:Collagenases; D020780:Matrix Metalloproteinase 9