Extracellular vesicles in AD-like pathology in HIV and its potential therapeutics

对38-60岁艾滋病毒感染者（PLWH）脑组织的研究显示， 与年龄匹配的HIV阴性受试者相比，淀粉样斑块和tau蛋白过度磷酸化。PLWH谁 接受抗逆转录病毒治疗（ART）的人寿命更长，但会经历与艾滋病毒相关的神经退行性疾病， 他们会变老2018年，美国51%的PLWH年龄在50岁或以上，在未来5-10年，这一人群 60多岁，正是老年痴呆症（AD）症状开始显现的黄金年龄。此外，本发明还 据报道，艾滋病毒感染导致的过早衰老会影响PLWH的神经认知。由于衰老是一个重大的风险 AD发展的一个因素和艾滋病毒可导致过早衰老，研究这种关系至关重要 艾滋病导致的衰老和AD之间的联系 与年龄匹配的艾滋病毒阴性受试者相比，对艾滋病毒感染者脑组织的研究 38-60岁的PLWH显示淀粉样蛋白斑块和tau过度磷酸化增加。然而，底层 HIV引起PLWH中AD相关神经变性和记忆障碍的机制不是 好好研究。此外，由于ARV不能穿过血脑屏障（BBB），目前的ARV 治疗方案不足以抑制大脑中的HIV，这可能进一步加剧神经退行性疾病。 老年艾滋病毒感染者的状况。我们的初步研究表明，细胞外囊泡（EV） 来源于HIV感染的巨噬细胞携带较高的促炎细胞因子和较低的抗氧化酶。 此外，来自HIV感染的巨噬细胞的这些EV暴露于SH-SY 5 Y神经元细胞引起增加的细胞毒性。 毒性、IL-1β水平和神经元损失（MAP 2）。我们还证明了由 鼻内途径可以绕过BBB并在脑中检测到。 此外，我们还证明了elvitegravir（一种抗逆转录病毒药物）可以被装载到电动汽车中并被递送。 在体外模型中穿过BBB。本建议将阐明艾滋病毒成分的作用， EV通过TXNIP炎症途径引起AD样病理。我们还将使用电动汽车作为 纳米载体，以改善姜黄素（TXNIP抑制剂）和EVG水平跨越BBB，从而有效地抑制 具有最小/可耐受药物毒性的炎症。

Studies of brain tissues from people living with HIV (PLWH) age from 38-60 years, showed increased amyloid plaques and tau hyperphosphorylation compared to age-matched HIV-negative subjects. PLWH who are on antiretroviral therapy (ART) live longer but experience neurodegenerative conditions related to HIV as they age. In 2018, 51% of PLWH in the U.S. were age 50 or older, and in the next 5-10 years, this population will be in their sixties, the prime age when Alzheimer’s disease (AD) symptoms begin to manifest. Further, premature aging with HIV infection is reported to affect neurocognition in PLWH. Since aging is a significant risk factor for AD development and HIV can cause premature aging, it's critically important to examine the relationship between HIV-induced aging and AD. Compared to age-matched HIV-negative subjects, studies of brain tissues from people living with HIV (PLWH) aged 38-60 showed increased amyloid plaques and tau hyperphosphorylation. However, the underlying mechanism by which HIV causes AD-associated neurodegeneration and memory impairment in PLWH is not well studied. Moreover, due to the inability of ARVs to cross the blood-brain barrier (BBB), the current ARV regimens are insufficient in suppressing HIV in the brain, which can further exacerbate neurodegenerative conditions in the aged HIV population. Our preliminary studies have shown that extracellular vesicles (EVs) derived from HIV-infected macrophages carry higher pro-inflammatory cytokines and low antioxidant enzymes. Further, exposure of these EVs from HIV-infected macrophages to SH-SY5Y neuronal cells caused increased toxicity, IL-1β levels, and neuronal loss (MAP2). We have also demonstrated that EVs administered by the intranasal route can bypass the BBB and be detected in the brain. Further, we showed that the elvitegravir (an antiretroviral drug) could be loaded into EVs and delivered across the BBB in an in vitro model. This proposal will elucidate the role of the HIV components packaged in EVs in causing AD-like pathology through the TXNIP inflammatory pathway. We will also use EVs as nanocarriers to improve curcumin (TXNIP inhibitor) and EVG levels across the BBB, thus effectively suppressing inflammation with minimal/tolerable drug toxicity.