The pathobiology of HIV dementia (HIVD) is only partly understood, however, evidence suggests that disruption of the blood brain barrier (BBB) may play a role. Structural and functional alterations in the BBB have been detected in association with HIVD, and these alterations would be expected to facilitate the ingress of both inflammatory cells and serum-derived toxins. Extracellular matrix proteins, including those which are critical to the integrity of the BBB, are regulated by an endogenous family of proteins called matrix metalloproteases (MMPs). These proteases are released not only by activated T cells and monocytes as they migrate through the BBB, but also by resident cells of the brain parenchyma. It has been shown that injection of MMPs into the parenchyma of the brain causes a disruption of the BBB, which is followed by leukocytic inflitration of the central nervous system (CNS). Moreover, MMPs produced within the brain parenchyma may have more direct effects on CNS structure and function in that extra cellular matrix proteins are known to affect synaptic structure as well as neuronal survival. In the present study, we will address the possibility that activated and HIV-1 infected monocytes release substances which can in turn increase the release of MMPs from resident cells of the CNS. We will also address the possibility that supernatants from activated and HIV-infected monocytes, as well as the MMPs that they induce, will affect the structure and function of an in vitro BBB model. These studies are novel in that the effects of supernatants from activated and HIV infected monocytes on MMP production by resident cells of the CNS are unknown, and in general, little is known about MMP regulation in the CNS. Also, the proposed studies will use both primary brain-derived HIV isolates, which differ from laboratory adapted strains, and normal human cells, which also differ significantly from those of rodent or tumor origin.
| Conant, Katherine; St Hillaire, Coryse; Nagase, Hideaki et al. (2004) Matrix metalloproteinase 1 interacts with neuronal integrins and stimulates dephosphorylation of Akt. J Biol Chem 279:8056-62 |
| Conant, Katherine; Haughey, Norman; Nath, Avindra et al. (2002) Matrix metalloproteinase-1 activates a pertussis toxin-sensitive signaling pathway that stimulates the release of matrix metalloproteinase-9. J Neurochem 82:885-93 |
