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

对38-60岁艾滋病毒携带者(PLWH)脑组织的研究表明， 与年龄匹配的HIV阴性受试者比较淀粉样斑块和tau过度磷酸化。PLWH世界卫生组织 接受抗逆转录病毒治疗(ART)的人寿命更长，但经历了与HIV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，在接下来的5-10年里，这一人口 将在60多岁，也就是阿尔茨海默病(AD)症状开始显现的黄金年龄。此外， 据报道，早衰和HIV感染会影响PLWH的神经认知。因为老龄化是一项重大风险 阿尔茨海默病的发病因素和艾滋病毒可导致过早衰老，研究两者之间的关系至关重要 HIV诱导的衰老和AD之间的关系。 与年龄匹配的艾滋病毒阴性受试者相比，对艾滋病毒携带者脑组织的研究 38-60岁(PLWH)患者表现为淀粉样斑块增多和tau过度磷酸化。然而，潜在的 HIV导致阿尔茨海默病患者AD相关神经变性和记忆障碍的机制尚不清楚 研究得很好。此外，由于抗逆转录病毒药物无法通过血脑屏障，目前的抗逆转录病毒药物 治疗方案不足以抑制大脑中的艾滋病毒，这可能会进一步加剧神经退行性变 老年艾滋病毒人群的状况。我们的初步研究表明，细胞外小泡(EVS) 来自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，将这些来自HIV感染的巨噬细胞的EV暴露于SH-SY5Y神经细胞会导致 毒性、IL-1β水平和神经元丢失(MAP2)。我们还证明了由 鼻腔途径可以绕过血脑屏障，在大脑中被检测到。 此外，我们还证明了elvitegravir(一种抗逆转录病毒药物)可以装载到电动汽车中并运送到EVS中。 在体外模型中跨越血脑屏障。这项提案将阐明包装在 EVS通过TXNIP炎症途径导致类AD病理改变。我们还将使用电动汽车作为 纳米载体可改善整个血脑屏障的姜黄素(TXNIP抑制剂)和EVG水平，从而有效地抑制 炎症，药物毒性最小/可耐受。

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.