PKR signaling in HIV-Associated Neurodegeneration

Burnham Institute For Medical Research, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): The mechanisms by which human immunodeficiency virus type-1 effects neural injury in HIV-associated dementia (HAD) remain largely unknown. It is thought that the HIV-1 envelope glycoprotein gp120 plays a role in the syndrome by inducing neurotoxicity, mediated in part by the undue glial secretion of tumor necrosis factor alpha and other potentially neurotoxic cytokines. PKR is an important pro-apoptotic kinase induced by TNF that triggers programmed cell death in a variety of cell types in response to stress signals. It has also been shown that PKR activates certain target molecules that are identical to those reported to be activated in gp120-induced neuronal cell death, such as p53 and NF-kappaB. Recent experiments that I have performed suggest that PKR is expressed at a low level in cultured cerebrocortical neurons, and it is significantly upregulated in response to gp120 treatment. Furthermore, I demonstrated that the inactivation of PKR in this culture is able to protect neurons against gp120 exposure. On the basis of these observations and other evidence, I propose to characterize and functionally validate the role of PKR in gp120-induced neurotoxicity and to elucidate the effector pathways by which it exerts its potentially destructive effects.