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Modulation of the Endocannabinoid System By Hiv Tat Protein

2020-06
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Modulation of the Endocannabinoid System By Hiv Tat Protein

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2020-06

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Despite the success of combined antiretroviral therapy (cART) in extending the lifespan and enhancing the quality of life for those infected with HIV, nearly half of the 37.9 million HIV-positive individuals experience some degree of neurocognitive impairment. These impairments are collectively termed HIV-associated neurocognitive disorders (HAND). HAND symptoms range from subtle difficulties in the tasks of daily living to severe functional impairment and dementia. cART effectively suppresses viral load and improves patient survival; however, while the severity is reduced, the prevalence of HAND remains high and may be increasing due to the prolonged lifespan of HIV patients. Currently, there are no effective treatments for HAND. HIV neurotoxicity is mainly mediated by inflammatory and excitotoxic agents released from infected macrophages and microglia. The HIV trans-activator protein Tat is one such agent that plays a major role in the neuropathogenesis of HAND. While cART suppresses viral replication, it does not halt the production of Tat once HIV has integrated into the host genome. Numerous studies have demonstrated that Tat causes excitotoxicity, which leads to a loss of spine density and altered network function; this synaptic dysfunction predicts marked impairments in learning and memory paradigms in various in vitro and in vivo models of HAND. Thus, it is essential to elucidate the mechanisms that cause and exacerbate neurotoxicity, in order to find effective therapeutic targets to ultimately treat HAND symptoms. A growing body of literature indicates that components of the endocannabinoid (eCB) system may be viable therapeutic targets. Across many models of neurological disorders that share a common pathophysiological pathway including excitotoxicity and neuroinflammation, activation of the eCB system attenuates detrimental cellular processes. Recent reports show that activating the eCB system protects against HIV-induced neurotoxicity, indicating that modulation of the eCB system may be a viable therapeutic approach to suppress the neuronal damage that underlies HAND. However, one important determinant of clinical outcome is the degree to which the target biological system is functional. Exposure to excitotoxic stimuli alters the eCB system; whether eCB signaling is altered in the presence of HIV is unknown. In this dissertation, I explore the effects of HIV Tat protein on eCB signaling in vitro. Using an electrophysiological approach, I determined that Tat impaires cannabinoid type 1 receptor (CB1R) function in a subset of neurons without affecting other components of the eCB system. Taken together, these results indicate that Tat specifically impairs CB1R-mediated presynaptic inhibition of glutamate release. This observation suggests that eCB-mediated neuroprotection may be reduced in vivo, possibly exacerbating synaptodendritic injury caused by HIV. Thus, this dissertation provides new insight into processes that further contribute to HIV-induced neurotoxicity and suggests that protecting or enhancing the neuroprotective eCB system may attenuate the symptoms of HAND.

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University of Minnesota Ph.D. dissertation. June 2020. Major: Neuroscience. Advisor: Stanley Thayer. 1 computer file (PDF); xi, 85 pages.

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Wu, Mariah. (2020). Modulation of the Endocannabinoid System By Hiv Tat Protein. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/216103.

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