PDF(Pubmed)
Abstract：
Extracellular vesicles (EVs) serve as pivotal mediators of intercellular communication in both health and disease, delivering biologically active molecules from vesicle-producing cells to recipient cells. In the context of HIV infection, EVs have been shown to carry the viral protein Nef, a key pathogenic factor associated with HIV-related co-morbidities. Despite this recognition, the specific localisation of Nef within the vesicles has remained elusive. This study addresses this critical knowledge gap by investigating Nef-containing EVs. Less than 1% of the total released Nef was associated with EVs; most Nef existed as free protein released by damaged cells. Nevertheless, activity of EV-associated Nef in downregulating the major cholesterol transporter ABCA1, a critical aspect linked to the pathogenic effects of Nef, was comparable to that of free Nef present in the supernatant. Through a series of biochemical and microscopic assays, we demonstrate that the majority of EV-associated Nef molecules are localised on the external surface of the vesicles. This distinctive distribution prompts the consideration of Nef-containing EVs as potential targets for immunotherapeutic interventions aimed at preventing or treating HIV-associated co-morbidities. In conclusion, our results shed light on the localisation and functional activity of Nef within EVs, providing valuable insights for the development of targeted immunotherapies to mitigate the impact of HIV-associated co-morbidities.
摘要：
细胞外囊泡（EV）是健康和疾病中细胞间通讯的关键介质，将生物活性分子从囊泡产生细胞递送到受体细胞。在艾滋病毒感染的背景下，电动汽车已被证明携带病毒蛋白Nef，与HIV相关共病相关的关键致病因素。尽管有这样的认可,Nef在囊泡中的特定定位仍然难以捉摸。本研究通过调查含Nef的电动汽车来解决这一关键的知识差距。少于1％的总释放Nef与EV相关；大多数Nef以受损细胞释放的游离蛋白形式存在。然而，EV相关的Nef在下调主要胆固醇转运蛋白ABCA1中的活性，这是与Nef的致病作用有关的一个关键方面，与上清液中存在的游离Nef相当。通过一系列生化和显微镜检测，我们证明了大多数与EV相关的Nef分子位于囊泡的外表面上。这种独特的分布促使人们考虑将含Nef的EV作为旨在预防或治疗HIV相关合并症的免疫治疗干预措施的潜在目标。总之,我们的结果揭示了Nef在电动汽车中的定位和功能活动，为开发靶向免疫疗法以减轻HIV相关合并症的影响提供有价值的见解。
