MMPs/TIMPs imbalances in the peripheral blood and cerebrospinal fluid are associated with the pathogenesis of HIV-1-associated neurocognitive disorders

Abstract

Abstract HIV-1-associated neurocognitive disorders (HAND) continue to be a major concern in the infected population, despite the widespread use of antiretroviral therapy. Growing evidence suggests that an imbalance between matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs) contributes to the pathogenesis of HAND. In our present study, we examined MMPs/TIMPs protein levels and MMPs enzymatic activities in both plasma and cerebrospinal fluid (CSF) samples from HIV-1 patients and HIV-1-negative controls. We found that imbalances between MMPs and TIMPs occurred in both the plasma and CSF of HIV-1 patients, especially those with neurocognitive disorders. In the plasma, the protein levels of MMP-2, TIMP-1, and TIMP-2, but not MMP-9, were increased in all HIV-1 patients when compared with HIV-1-negative controls. The enzymatic activity of both MMP-2 and MMP-9 was increased in all HIV-1 patients. Particularly, the ratio of MMP-2/TIMP-2 was significantly increased in HAND patients, not in patients without neurocognitive disorders. In the CSF, MMP-2 activity was increased, but the ratio of MMP-2/TIMP-2 was not altered. De novo induction and activation of MMP-9 in the CSF of HAND patients was particularly prominent. The imbalances between MMPs and TIMPs in the blood and CSF were related to the altered profiles of inflammatory cytokines/chemokines and monocyte activation. In addition, HIV-1 plasma directly damaged a blood brain barrier (BBB) model, leading to increased BBB permeability and vigorous transmigration of monocytes. Thus, the increased ratio of MMP-2/TIMP-2 in the peripheral blood and de novo induction and activation of MMP-9 in the CSF are significant in HAND patients and may be biomarkers for HAND.