Human immunodeficiency virus (HIV) associated sensory neuropathies (H1V-SN) are major neurological complications of the HIV infection and despite the use of highly active antiretroviral therapy (HAART), the incidence and prevalence of this often painful complication of HIV infections remains high. HIV associated sensory neuropathies are often divided into distal symmetric polyneuropathy (DSP) due to the HIV infection per se and antiretroviral toxic neuropathy (ATM) due to the use of dideoxynucleoside (DDX) drugs. Clinically both conditions are similar and likely to have a synergistic role in the pathogenesis of HIV-SN. Currently, there are no therapies aimed at reversing or slowing the progression of these painful neuropathies that affect the quality of life of HIV/AIDS patients. In the previous cycle of this grant, we have developed in vitro models of ATN and DSP and identified a novel endogenous neuroprotective pathway that exist in the peripheral nervous system (PNS). This progress is coupled to the development of a transgenic mouse model of HIV-SN that will be useful in examining the underlying mechanisms of HIV-SN. Furthermore, we identified, erythropoietin as a potential therapeutic target for HIV-SN. In the current application we propose to continue our investigations into the cellular mechanisms of distal axonal degeneration in transgenic mice treated with DDX drugs as well as molecular mechanisms by which HIV proteins and DDX drugs cause neuronal dysfunction and axonal degeneration. We will examine the role of various mitochondrial pathways involved in neuronal dysfunction and death in mediating HIV envelope protein gp120 and DDX neurotoxicity. We will use the animal model of HIV-SN to develop biomarkers of treatment effects in HIV-SN. Finally, we will explore the therapeutic potential of neurotrophic genes regulated by hypoxia inducible factor (HIF), activators of the hsp70 pathway, and cyclophilin ligands to develop novel therapies for HIV-associated sensory neuropathies. These goals are highly relevant to the patient population we serve in the clinic as there are no effective therapies for the painful sensory neuropathy associated with HIV infection and use of DDX drugs. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043991-06
Application #
7483183
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2002-04-01
Project End
2012-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
6
Fiscal Year
2008
Total Cost
$410,000
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Cashman, Christopher R; Höke, Ahmet (2015) Mechanisms of distal axonal degeneration in peripheral neuropathies. Neurosci Lett 596:33-50
Höke, Ahmet (2014) Augmenting glial cell-line derived neurotrophic factor signaling to treat painful neuropathies. Proc Natl Acad Sci U S A 111:2060-1
Zhu, Jing; Chen, Weiran; Mi, Ruifa et al. (2013) Ethoxyquin prevents chemotherapy-induced neurotoxicity via Hsp90 modulation. Ann Neurol 74:893-904
Hoke, Ahmet (2012) Animal models of peripheral neuropathies. Neurotherapeutics 9:262-9
Lehmann, Helmar C; Chen, Weiran; Mi, Ruifa et al. (2012) Human Schwann cells retain essential phenotype characteristics after immortalization. Stem Cells Dev 21:423-31
Keswani, Sanjay C; Bosch-Marce, Marta; Reed, Nicole et al. (2011) Nitric oxide prevents axonal degeneration by inducing HIF-1-dependent expression of erythropoietin. Proc Natl Acad Sci U S A 108:4986-90
Lehmann, Helmar C; Chen, Weiran; Borzan, Jasenka et al. (2011) Mitochondrial dysfunction in distal axons contributes to human immunodeficiency virus sensory neuropathy. Ann Neurol 69:100-10
Lehmann, Helmar C; Höke, Ahmet (2010) Schwann cells as a therapeutic target for peripheral neuropathies. CNS Neurol Disord Drug Targets 9:801-6
Vivithanaporn, P; Heo, G; Gamble, J et al. (2010) Neurologic disease burden in treated HIV/AIDS predicts survival: a population-based study. Neurology 75:1150-8
Melli, Giorgia; Höke, Ahmet (2009) Dorsal Root Ganglia Sensory Neuronal Cultures: a tool for drug discovery for peripheral neuropathies. Expert Opin Drug Discov 4:1035-1045

Showing the most recent 10 out of 21 publications