This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 overexpression of specific chemokines and receptors. 2) The production of cytokines by macrophages in nerves drives uninjured C fiber nociceptors 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 antriretrovirals injure sensory nerve fibers through mitochondiral dysfunction, and neuropathic pain will correlate with levels of mitochondiral DNA. 5) Chemokine receptors on sensory neurons are involved in the induction of pain in HIV-SN. We will conduct a prospective study in two parallel cohorts of adult HIV-infected patinets. We will determine the incidence and prevalence of LATNl, 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 out studies of the immunopathology of HIV-SN, using our extensive tissue collections to define the relationship of chemokine upregulation to neuropathic pain.
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