Neurocognitive implications of cannabidiol (CBD) while aging with HIV

项目摘要 联合抗逆转录病毒疗法（cART）的成功极大地提高了人们的预期寿命 艾滋病毒携带者这导致临床观察到显著的年龄相关的神经认知功能障碍， 艾滋病毒感染者老龄化的并发症。HIV相关的炎症与 即使在cART治疗的个体中，也会出现过早衰老和年龄相关合并症风险增加。目前， 艾滋病毒感染者出于娱乐或医疗目的使用大麻的比率高于一般人， 人口然而，大麻素在艾滋病毒和衰老的背景下仍然是临床前未探索的。如使用 老年艾滋病毒感染者中的医用大麻使用率继续上升，迫切需要调查 大麻素在艾滋病毒老化过程中的后果。本提案的目标是揭示有益于 大麻素对艾滋病毒和艾滋病毒诱导的老年小鼠神经认知缺陷的有害影响。已经 大麻二酚（CBD）可以改善小鼠的空间和识别记忆，并减少焦虑。 阿尔茨海默病模型，表明其对年龄相关性痴呆的治疗潜力。所以我们 假设暴露于CBD将调节衰老小鼠的神经炎症和认知缺陷， 艾滋病。为了检验这一假设，将C57 BL/6 J雄性和雌性成年小鼠（16月龄）感染 嗜鼠性HIV，EcoHIV。8周后（18个月大时），将暴露一部分EcoHIV感染小鼠 单独CBD，单独抗逆转录病毒药物，以及伴随CBD和抗逆转录病毒药物21天。在具体目标1中， CBD将调节与艾滋病毒和年龄相关的认知缺陷，特别是记忆和学习 功能，通过新物体识别测试和Y-迷宫行为测试测量。在具体目标2中， 证明CBD暴露将调节神经炎症，神经胶质表型和细胞衰老， 在特异性目标1中回收的EcoHIV感染和老年小鼠的死后脑组织。实验 在这项建议中描述的将使我们能够确定可能介导的分子机制， 大麻素暴露在艾滋病毒感染的老年大脑中的后果。这个项目的最终目标是 确定一个潜在的治疗靶点，可以减少与年龄相关的神经退行性缺陷， 与慢性HIV感染有关。

PROJECT SUMMARY The success of combined antiretroviral therapy (cART) has drastically improved the life expectancy of people living with HIV. This has resulted in the clinical observations of significant age-related neurocognitive complications among the population aging with HIV. HIV-associated inflammation has been implicated in premature aging and increased risk of age-associated comorbidities even in cART-treated individuals. Currently, people living with HIV are using cannabis, for recreational or medical purposes, at higher rates than the general population. However, cannabinoids in the context of HIV and aging remain preclinically unexplored. As the use of medical cannabis among older HIV individuals continues to rise, there is an urgent need to investigate the consequences of cannabinoids during aging with HIV. The goal of this proposal is to unravel the beneficial versus the detrimental effects of cannabinoids on HIV and HIV-induced neurocognitive deficits in aged mice. It has been shown that cannabidiol (CBD) improves both spatial and recognition memory and decreases anxiety in a mouse model of Alzheimer’s disease, suggesting its therapeutic potential for age‐related dementia. Therefore, we hypothesize that exposure to CBD will modulate neuroinflammation and cognitive deficits in mice that aged with HIV. To test this hypothesis, C57BL/6J male and female adult mice (at 16-months old) will be infected with the mouse-tropic HIV, EcoHIV. After 8 weeks (at 18-months old), a subset of EcoHIV-infected mice will be exposed to CBD alone, antiretrovirals alone, and concomitant CBD and antiretrovirals for 21 days. In Specific Aim 1, we posit that CBD will modulate HIV- and age-associated cognitive deficits, specifically memory, and learning functions, measured by the novel object recognition test and the Y-maze behavioral test. In Specific Aim 2, we posit that CBD exposure will modulate neuroinflammation, glial phenotypes, and cellular senescence in postmortem brain tissue of EcoHIV-infected and aged mice recovered in Specific Aim 1. The experiments described in this proposal will allow us to determine the molecular mechanisms that could mediate the consequences of cannabinoids exposure in the HIV-infected aged brain. The ultimate goal of this project is to identify a potential therapeutic target that could reduce age-related neurodegenerative deficits associated with chronic HIV infection.