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. Neurological complications in human immunodeficiency virus (HIV) infection are common and are significant sources of mortality and morbidity. Effective antiretroviral therapies (ART) and preventive therapies for many opportunistic infections have led to a recent decline in the incidence of certain neurological diseases, such as central nervous system infections, and an improvement in psychomotor performance. At the same time, ART has led to an increasing pool of long-term survivors with HIV disease and this may in turn lead to an increase in the prevalence of neurological conditions, including HIV-associated dementia (HAD) and peripheral neuropathy. These neuropathies appear to be multi-factorial in etiology and are associated with long-term nucleoside reverse transcriptase inhibitor (NRTI) antiretroviral therapy and with more advanced HIV disease. Our preliminary data has shown that brain cerebrum and cerebellum mitochondria are sensitive to NRTIs. Our hypothesis is that certain neurotoxic NRTIs, like zalcitabine, didanosine, or stavudine and/or HIV infection are contributing to mitochondrial dysfunction of neurons, microglia, and astrocytes by decreasing energy metabolism and increasing oxidative stress, and apoptosis. We postulate that the mechanism for this dysfunction is a decrease in mitochondrial DNA (mtDNA) and/or changes in oxidative phosphorylation (OXPHOS) enzyme activities, leading to a decrease in adenosine triphosphate (ATP) levels. We propose to examine this hypothesis by infecting primary human neurons or neuroglial cells with HIV with or without human equivalent drug doses used in ART, and studying mitochondrial morphology, ATP production, oxidative stress responses, and apoptosis. Studies will also be conducted using a human mitochondrial spotted array chip to evaluate gene expression of this hypothesis and to pursue other genes involved in these neuropathies.
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