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Brain Behav Immun. 2017 Oct;65:161-172. doi: 10.1016/j.bbi.2017.04.024. Epub 2017 May 6.

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

Author information

1
Department of Pathophysiology, Key Laboratory of the State Administration of Traditional Chinese Medicine, Medical College of Jinan University, Guangzhou, Guangdong 510632, China; Indiana Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
2
Indiana Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
3
Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
4
Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
5
Department of Pathophysiology, Key Laboratory of the State Administration of Traditional Chinese Medicine, Medical College of Jinan University, Guangzhou, Guangdong 510632, China; Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong 510632, China. Electronic address: dongjunbox@163.com.
6
Indiana Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, United States; Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States. Electronic address: andyu@iupui.edu.

Abstract

HIV-1-associated neurocognitive disorders (HAND) continue to be a major concern in the infected population, despite the widespread use of combined antiretroviral therapy (cART). 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 protein levels and enzymatic activities of MMPs and TIMPs in both plasma and cerebrospinal fluid (CSF) samples from HIV-1 patients with or without HAND and HIV-1-negative controls. Imbalances between MMPs and TIMPs with distinct patterns were revealed in both the peripheral blood and CSF of HIV-1 patients, especially those with HAND. In the peripheral blood, the protein levels of MMP-2, MMP-9, TIMP-1, TIMP-2, and the enzymatic activities of MMP-2 and MMP-9 were increased in HIV-1 patients with or without HAND when compared with HIV-1-negative controls. The enzymatic activity of MMP-2, but not MMP-9, was further increased in plasma samples of HAND patients than that of HIV-1 patients without HAND. Notably, the ratio of MMP-2/TIMP-2 in plasma was significantly increased in HAND patients, not in patients without HAND. 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 these individuals. In addition, plasma from HIV-1 patients directly induced integrity disruption of an in vitro blood-brain barrier (BBB) model, leading to increased BBB permeability and robust transmigration of monocytes/macrophages. These results indicate that imbalances between MMPs and TIMPs are involved in BBB disruption and are implicated in the pathogenesis of neurological disorders such as HAND in HIV-1 patients.

KEYWORDS:

BBB; HIV-1; HIV-1-associated neurocognitive disorders; MMPs; Neuropathy; TIMPs

PMID:
28487203
PMCID:
PMC5793222
DOI:
10.1016/j.bbi.2017.04.024
[Indexed for MEDLINE]
Free PMC Article

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