Effects of Antiretrovirals on Neuronal Health: Screening ARVs for Neurotoxicity

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DESCRIPTION (provided by applicant): Approximately 50% of HIV positive veterans develop HIV associated neurocognitive disorders, or HAND, despite adequate anti-HIV drug therapy. The neurologic disease associated with HIV infection ranges from asymptomatic neurocognitive impairment, only detected by sophisticated neuropsychological testing, to frank dementia. In industrialized nations like the United States, retroviral pharmacotherapy has reduced the incidence of severe dementia due to HIV infection, but the prevalence of HAND has unexpectedly risen (especially among the milder forms). The reason(s) for this is unclear; however, new data suggest that the antiretroviral agents (ARVs) used to combat HIV infection may independently exert central nervous system (CNS) toxicities and contribute to this increased prevalence of adverse neurologic symptomatology. The milder forms of HAND are more common, more insidious in their onset and can detrimentally impact a veteran's ability to remain healthy and financially secure. Surprisingly, the direct effects of ARV on functional signaling of CNS neurons has yet to be examined. Through this funding, we have the opportunity to fill that knowledge gap. The majority of the accumulated evidence that implicates anti-HIV drugs as potentially involved in cognitive dysfunction is inferred from in vitr experiments involving sensory neurons or derived from clinical studies that are mostly observational in their design. Understanding the mechanisms of the potential adverse effects of our treatments for HIV is the only way to minimize their negative impact on health. The primary goal of the proposed research is to examine ARVs for CNS neuronal toxicity in the absence of inflammation or infection. This will be investigated through physiological, anatomical, and behavioral approaches. By determining mechanisms of neurotoxicity in preclinical investigations, we can begin to develop rational treatments for these complications of ARV therapy and to adapt pharmacologic regimens to involve less toxic CNS effects in patients with existing cognitive dysfunction. As HAND may first manifest as mild cognitive impairment in spatiotemporal memory tasks, our research efforts will focus on these cortical brain regions known to be closely associated with memory tasks. The underlying hypotheses of the proposed work is that despite their efficacy in reducing HIV load, certain ARVs clinically associated with peripheral neuropathy will also impair normal cortical neuron anatomy, physiology, and synaptic transmission and these neurophysiological effects will lead to measurable changes on memory-associated tasks either acutely or via chronic exposure. To test my hypotheses, I am proposing to subject a diverse subset of the ARVs (8 separate drugs) to a battery of in vitro and ex vivo experiments in order to determine the effects of these drugs on the dendritic branching, excitability, and network activity of cortical neurons; thus establishing a biophysical profile of potentially toxic ARV. I will then validate biophysical predictors of neurotoxicity using in vivo behavioral testing of memory disruption. And then establish an efficient biophysical screen for ARV-mediated neurotoxicity using the simplest biophysical testing modality which predicts the most severe memory impairments measured in the whole animal. Finally, I will apply only the necessary screening tools to all of the commonly prescribed ARVs to streamline the method of neurotoxicity detection. Through this mentored award, I will extend my laboratory skills beyond my background in neurophysiology to include behavioral and neuroanatomical techniques. Once armed with the necessary toolbox, I intend to develop an independent science program focusing on translating pharmacological testing to guiding clinical decisions in the neurosciences.