An imbalance between MMPs and TIMPs plays a critical role in the pathogenesis of HIV-associated neurocognitive disorders

HIV-associated neurocognitive disorders (HAND) affects approximately 50% of HIV-infected individuals, and disruption of the blood brain barrier (BBB) has been observed in individuals with HAND. One of the underlying mechanisms of BBB breakdown is an imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs), which has not been fully explored in HAND. In our present study, we used ELISA and zymography assays to examine the protein levels and enzyme activities of MMPs and/or TIMPs in plasma from a total of 59 HIV-positive individuals and 16 uninfected controls. We found that the concentration and enzyme activity of MMP-2 and MMP-9, two of the most important members of the MMP family, were increased in the plasma of HIV patients compared to HIV-negative controls. Plasma levels of TIMP-1 and TIMP-4 were not affected, while TIMP-3 was significantly increased in HIV patients. Strikingly, TIMP-2 was significantly down-regulated in HIV-1 patients. We also showed that neural cells, especially astrocytes, were able to release both MMPs and TIMPs, and such secretion was regulated by inflammatory factors like IL-1β or growth factors like TGF-β1. Furthermore, we found that TIMP-2 played a dual role on proMMP-2 activation via the ternary complex of MT1-MMP/TIMP-2/proMMP-2 on the surface of astrocytes, as low concentrations of TIMP-2 activated proMMP-2 and high concentrations inhibited proMMP-2 activity. In summary, our results demonstrate that decreased TIMP-2 found in HIV patients enhances MMP-2 activity, which is associated with BBB breakdown in HIV patients. Exogenous administration of TIMP-2 to maintain MMPs/TIMP-2 homeostasis may represent a potential therapy for HAND.