Peripheral neurotoxicity by the HIV-1 coat protein gp120

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): HIV-associated sensory neuropathy (HIV-SN) is now recognized as the most common neurological complication of HIV infection, symptomatically affecting one-third of AIDS patients, including children and adults. Little attention has so far been devoted to exploring the pathogenesis of this very painful disorder, which presently has no effective treatment. Pathologically, HIV-SN is characterized by loss of Dorsal Root Ganglion (DRG) sensory neurons, DRG infiltration by HIV-infected macrophages, and a 'dying back' sensory neuropathy. Akin to the situation in HIV dementia, neuronal infection by HIV occurs rarely, if at all, in the DRG of patients with HIV-SN. We thus hypothesize that the loss of DRG neurons and the sensory axonopathy seen in HIV-SN result from neurotoxicity by soluble mediators released by HIV-infected macrophages present in the DRG of these patients. These mediators include secreted viral proteins such as the HIV-1 envelope glycoprotein gp120, which we have shown recently is an extremely potent neurotoxin in rat embryonic DRG cultures. We postulate that gp120 released by H IV-infected macrophages in the DRG, causes both direct and indirect peripheral neurotoxicity via chemokine receptor ligation on neurons, macrophages and Schwann cells. Furthermore, as the severity of neuropathology does not always mirror the degree of pain that so dominates the symptomatology of HIV-SN, we suggest that gp120 may contribute to the pathogenesis of neuropathic pain by directly activating nociceptive neurons. This project aims to characterize gp120 neurotoxicity in human fetal DRG cultures, and elucidate the pathogenetic mechanisms leading to this neurotoxicity, so that therapeutic strategies can be devised. A major strength of our proposal is our use of human tissues to study a disease that only affects humans.