The principal neurological complication of HIV/AIDS observed in the developed world is currently peripheral neuropathy, usually manifested as distal polyneuropathy (DSP) or antiretroviral toxic neuropathy (ATN). This proposal examines the role of lentivirus molecular diversity in relation to the development of DSP, using multiple infectious biological strains and recombinant viruses of feline immunodeficiency virus (FIV). Based on our preliminary studies and earlier reports, we hypothesize that infection of peripheral nerves by select FIV strains, expressing different env sequence contributes to the development of DSP due to immune activation within the nerve together with concomitant systemic immune suppression. Moreover, viral heterogeneity and load within the nerve determine the severity of DSP, which can be abrogated or exacerbated with specific antiretroviral drugs. To investigate the mechanisms by which viral diversity contributes to DSP, we propose to use a well defined in vivo model of lentivirus infection in which animals infected with different strains or molecular clones of FIV are assessed neurobehaviorally, electrophysiologically, morphologically and immunologically in conjunction with analyses of viral heterogeneity and load in peripheral nerve and other organs. To support these in vivo studies, we will also explore the role of FIV env-mediated neurotoxicity using a dorsal root ganglia-derived culture system, allowing us to dissect the relative contributions of individual cell types to the pathogenesis of DSP including macrophages and Schwann cells. From these studies, we expect to gain insights into this common neurological complication in terms of lentivirus-induced neurovirulence and pathogenic host responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS046262-01
Application #
6599353
Study Section
Special Emphasis Panel (ZMH1-BRB-P (03))
Program Officer
Nunn, Michael
Project Start
2002-09-30
Project End
2005-06-30
Budget Start
2002-09-30
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$234,398
Indirect Cost
Name
University of Calgary
Department
Type
DUNS #
207663915
City
Calgary
State
AB
Country
Canada
Zip Code
T2 1-N4
Zhu, Yu; Antony, Joseph M; Martinez, Jose A et al. (2007) Didanosine causes sensory neuropathy in an HIV/AIDS animal model: impaired mitochondrial and neurotrophic factor gene expression. Brain 130:2011-23
Pettersen, Jacqueline A; Jones, Gareth; Worthington, Catherine et al. (2006) Sensory neuropathy in human immunodeficiency virus/acquired immunodeficiency syndrome patients: protease inhibitor-mediated neurotoxicity. Ann Neurol 59:816-24
Cornblath, David R; Hoke, Ahmet (2006) Recent advances in HIV neuropathy. Curr Opin Neurol 19:446-50
Jones, Gareth; Zhu, Yu; Silva, Claudia et al. (2005) Peripheral nerve-derived HIV-1 is predominantly CCR5-dependent and causes neuronal degeneration and neuroinflammation. Virology 334:178-93
Zhu, Yu; Jones, Gareth; Tsutsui, Shigeki et al. (2005) Lentivirus infection causes neuroinflammation and neuronal injury in dorsal root ganglia: pathogenic effects of STAT-1 and inducible nitric oxide synthase. J Immunol 175:1118-26
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; Leitz, Gerhard J; Hoke, Ahmet (2004) Erythropoietin is neuroprotective in models of HIV sensory neuropathy. Neurosci Lett 371:102-5
Hoke, Ahmet; Cornblath, David R (2004) Peripheral neuropathies in human immunodeficiency virus infection. Suppl Clin Neurophysiol 57:195-210
Keswani, Sanjay C; Buldanlioglu, Ulas; Fischer, Angela et al. (2004) A novel endogenous erythropoietin mediated pathway prevents axonal degeneration. Ann Neurol 56:815-26