Presence of Matrix Metalloproteinase‐9 Activity in the Cerebrospinal Fluid of Human Immunodeficiency Virus—Infected Patients

Abstract

To determine whether matrix metalloproteinase (MMP)-9 is a potential mediator involved in the frequently detected blood-brain barrier leakage in human immunodeficiency virus (HIV)-infected patients, zymography was used to detect MMP-9 activity in cerebrospinal fluid (CSF) samples of 80 HIV-infected patients and of 10 control patients. CSF MMP-9 activity was detected in 40% of HIV-infected patients (but not in controls) and was significantly more frequent in HIV-infected patients than in those without neurologic deficits (50% vs. 13.6%). The frequency of CSF MMP-9 activity did not significantly differ between neurologically symptomatic HIV-infected patients with or without opportunistic central nervous system disease (51.6% vs. 48.1%). Additionally, the presence of CSF MMP-9 activity in HIV-infected patients was associated with an increased CSF white blood cell count and an elevated CSF-to-serum albumin ratio, suggesting that it may play a role in blood-brain/CSF barrier leakage in HIV-infected patients.

Mononuclear Phagocyte Differentiation, Activation, and Viral Infection Regulate Matrix Metalloproteinase Expression: Implications for Human Immunodeficiency Virus Type 1-Associated Dementia

“…Importantly, our assays examine MMP-9 production on a single-cell basis, and the results were confirmed in multiple donors. These results appear to be at odds with previously published reports (9,11,36,54,59). These studies assayed biological material such as patient plasma or cerebrospinal fluid to show net increases in MMP-9 production, but could not detect whether higher production by each cell was occurring.…”

HIV-1 glycoprotein 120 induces the MMP-9 cytopathogenic factor production that is abolished by inhibition of the p38 mitogen-activated protein kinase signaling pathway

“…By degrading extracellular matrix proteins, such as fibronectin and collagen IV, 26 MMPs contribute to demyelinization processes in the CNS, the breaking of the blood-brain barrier, and leukocyte migration through the endothelial barrier and tissues. 25 These observations agree with the reported data in which MIP-1␣, MIP-1␤, and, to a lesser extent, RANTES promote the secretion of pro-MMP-9 by T lymphocytes.…”

“…27 The presence of MMP-9 was reported in cerebrospinal fluid of HIVinfected patients. 26,28 In rapidly progressing simian immunodeficiency virus-infected monkeys, high expression of MMP-9 was correlated to both motor and cognitive deficits; in contrast, low progressors exhibited low levels of MMP-9, similar to uninfected control. 29 In addition, in vitro studies reported evidence that HIV itself, or at least the HIV Tat or Nef proteins directly promote MMP-9 secretion.…”

“…MMPs have been shown to degrade constituents of the extracellular matrix such as collagens, 25 favoring (1) blood-brain barrier leakage 26 and (2) infiltration by activated or infected cells. Indeed, gp41, the transmembrane component of the HIV envelope, has been reported to induce MMP-2 overproduction by nerve cells, resulting in the destruction of the extracellular matrix in vivo or in vitro.…”

Identification of a Matrix-Degrading Phenotype in Human Tuberculosis In Vitro and In Vivo

“…MMP-9 is not normally present in cerebrospinal fluid (CSF), but has been detected in patients with Lyme disease (11), viral meningitis (12), human T cell lymphotrophic virus-1-associated myelopathy (13), and multiple sclerosis (14,15). MMP-9 was detected in 40% of patients with HIV infection and more commonly in cases with neurological deficit (16). CSF MMP-9 concentrations were elevated in patients with bacterial meningitis and fell during recovery (17).…”