INTERFERON-GAMMA INHIBITS HIV-INDUCED INVASIVENESS OF MONOCYTES

HIV-infected monocytes form highly invasive network on basement membra ne matrix and secrete high levels of 92-kd metalloproteinase (MMP-9), an enzyme that degrades basement membrane proteins. In the present stu dy, using matrigel as a model basement membrane system, we demonstrate that treatment of human immunodeficiency virus (HIV)-infected monocyt es with interferon-gamma at 50 U/ml inhibited the ability of infected monocytes to form an invasive network on matrigel and their invasion t hrough the matrigel matrix. These effects were associated with a signi ficant reduction in the levels of MMP-9 produced by HIV-infected monoc ytes treated with interferon-gamma 1 day prior to infection with HIV a s compared with that of untreated HIV-infected monocytes. Monocytes tr eated with interferon-gamma 1 day after HIV infection showed the prese nce of integrated HIV sequences; however, the levels of MMP-9 were sub stantially 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 increa sed invasiveness or high MMP-9 production, suggesting that regulation of metalloproteinase by monocytes was independent of CD4-gp120 interac tions and required active virus infection. Furthermore, addition of in terferon-gamma to monocytes on day 10 after infection inhibited MMP-9 production by more than threefold with no significant reduction of vir us replication. These results indicate that the mechanism of interfero n-gamma-induced down-regulation of MMP-9 levels and reduced monocyte i nvasiveness may be mediated by a mechanism independent of antiviral ac tivity of IFN-gamma in monocytes. Down-regulation of MMP-9 in HIV-infe cted monocytes by interferon-gamma may play an important role in the c ontrol of HIV pathogenesis.