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.
|Höke, Ahmet; Morris, Michael; Haughey, Norman J (2009) GPI-1046 protects dorsal root ganglia from gp120-induced axonal injury by modulating store-operated calcium entry. J Peripher Nerv Syst 14:27-35|
|Chen, Weiran; Mi, Ruifa; Haughey, Norman et al. (2007) Immortalization and characterization of a nociceptive dorsal root ganglion sensory neuronal line. J Peripher Nerv Syst 12:121-30|
|Keswani, Sanjay C; Jack, Christelene; Zhou, Chunhua et al. (2006) Establishment of a rodent model of HIV-associated sensory neuropathy. J Neurosci 26:10299-304|
|Melli, Giorgia; Keswani, Sanjay C; Fischer, Angela et al. (2006) Spatially distinct and functionally independent mechanisms of axonal degeneration in a model of HIV-associated sensory neuropathy. Brain 129:1330-8|
|Cornblath, David R; Hoke, Ahmet (2006) Recent advances in HIV neuropathy. Curr Opin Neurol 19:446-50|
|Hoke, Ahmet; Keswani, Sanjay C (2005) Neuroprotection in the PNS: erythropoietin and immunophilin ligands. Ann N Y Acad Sci 1053:491-501|
|Keswani, Sanjay C; Buldanlioglu, Ulas; Fischer, Angela et al. (2004) A novel endogenous erythropoietin mediated pathway prevents axonal degeneration. Ann Neurol 56:815-26|