With recent declines in the incidence rates of HIV-associated dementia and CNS opportunistic infections, sensory neuropathies (HIV-SN) have become the commonest neurological disorders associated with AIDS. These include distal sensory polyneuropathy (DSP) and antiretroviral toxic neuropathy (ATN) and affect up to 30% of patients with advanced HIV disease. Pedal pain is prominent, but the underlying pathophysiological mechanisms remain undefined. There is limited information about the determinants and characteristics of sensory neuropathy related to ATN. Our underlying hypotheses are that: 1) the critical pathophysiological mechanisms underlying HIV-SN involve the over expression of specific chemokines and receptors. 2) The production of cytokines by macrophages in nerves drives uninjured C fiber coreceptors to spontaneous firing, leading to neuropathic pain. 3) The severity of neuropathic pain will be amplified by macrophage products in :nerves, and will correlate with circulating immune activation markers. 4) Neurotoxic antiretrovirals injure sensory nerve fibers through mitochondrial dysfunction, and neuropathic pain will correlate with levels of mitochondrial DNA. 5) Chemokine receptors on sensory neurons are involved in the induction of pain in HIV-SN. We will conduct a prospective study in a two parallel cohorts of adult HIV-infected patients. We will determine the incidence and prevalence of ATN, and delineate its pain characteristics, natural history, risk factors, predictive markers and mechanisms. Our long-term goal is to identify, prevent or treat HIV-SN. We will examine structural changes in epidermal nerves with skin biopsy, and functional changes in large and small caliber nerve fibers using quantitative sensory testing. Novel techniques developed by our collaborators at MU will be used to assess mitochondrial DNA levels after varying exposures to DDX agents. We will extend our studies of the immunopathology of HIV-SN, using our extensive tissue collections to define the relationship of chemokine upregulation to neuropathic pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS044807-01
Application #
6553921
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Nunn, Michael
Project Start
2002-07-19
Project End
2007-05-31
Budget Start
2002-07-19
Budget End
2003-05-31
Support Year
1
Fiscal Year
2002
Total Cost
$488,808
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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