Nef Secretion into Extracellular Vesicles or Exosomes Is Conserved across Human and Simian Immunodeficiency Viruses.
Nef Secretion into Extracellular Vesicles or Exosomes Is Conserved across Human and Simian Immunodeficiency Viruses.
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DOI：
10.1128/mbio.02344-17
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发表时间：
2018-02-06
期刊：
影响因子：
6.4
通讯作者：
Dittmer DP
中科院分区：
文献类型：
--
作者：
McNamara RP;Costantini LM;Myers TA;Schouest B;Maness NJ;Griffith JD;Damania BA;MacLean AG;Dittmer DP
细胞外囊泡（EV）或外泌体与感染和癌症的病理生理学有关。由猿猴免疫缺陷病毒 (SIV) 和人类免疫缺陷病毒 (HIV) 编码的负调节因子 (Nef) 在艾滋病进展和损害内体运输中发挥着关键作用。 HIV-1 Nef 是否可以装载到 EV 中一直是争议的话题，并且对于 SIV Nef 和 EV 之间的联系一无所知。我们发现 SIV 和 HIV-1 Nef 蛋白均存在于来自培养细胞的亲和纯化的 EV 中，以及来自 SIV 感染的猕猴的 EV 中。 Nef 阳性 EV 具有功能性，即能够进行膜融合并将其内容物沉积到受体细胞中。 EV 能够将 Nef 转移到受体细胞中。这表明 Nef 很容易进入外泌体生物合成途径，而 HIV 病毒体则在质膜上组装。它提出了慢病毒影响未感染和不可感染（即 CD4 阴性）细胞的新机制。细胞外囊泡（EV）将生物活性物质从一个细胞转移到另一个细胞，无论是在邻近的微环境中还是进一步去除。 EV 还包装病毒 RNA、microRNA 和蛋白质，这有助于感染的病理生理学。在本报告中，我们表明，人类免疫缺陷病毒（HIV）和猿猴免疫缺陷病毒（SIV）都将病毒编码的 Nef 蛋白整合到 EV 中，包括在感染 SIV 的猕猴血液中循环的 EV，这提出了一种将 Nef 转移到幼稚细胞甚至其他非感染细胞的新机制。 Nef 对于病毒复制来说是可有可无的，但对于艾滋病体内的进展至关重要。证明 Nef 掺入 EV 是跨物种保守的，这表明 EV 是 HIV 病理生理学的新介质。它可以帮助解释 HIV 对 CD4 阴性细胞的生物效应，并且 EV 可以成为疾病进展的生物标志物。
Extracellular vesicles (EVs) or exosomes have been implicated in the pathophysiology of infections and cancer. The negative regulatory factor (Nef) encoded by simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) plays a critical role in the progression to AIDS and impairs endosomal trafficking. Whether HIV-1 Nef can be loaded into EVs has been the subject of controversy, and nothing is known about the connection between SIV Nef and EVs. We find that both SIV and HIV-1 Nef proteins are present in affinity-purified EVs derived from cultured cells, as well as in EVs from SIV-infected macaques. Nef-positive EVs were functional, i.e., capable of membrane fusion and depositing their content into recipient cells. The EVs were able to transfer Nef into recipient cells. This suggests that Nef readily enters the exosome biogenesis pathway, whereas HIV virions are assembled at the plasma membrane. It suggests a novel mechanism by which lentiviruses can influence uninfected and uninfectable, i.e., CD4-negative, cells. Extracellular vesicles (EVs) transfer biologically active materials from one cell to another, either within the adjacent microenvironment or further removed. EVs also package viral RNAs, microRNAs, and proteins, which contributes to the pathophysiology of infection. In this report, we show that both human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) incorporate the virus-encoded Nef protein into EVs, including EVs circulating in the blood of SIV-infected macaques and that this presents a novel mechanism of Nef transfer to naive and even otherwise non-infectable cells. Nef is dispensable for viral replication but essential for AIDS progression in vivo. Demonstrating that Nef incorporation into EVs is conserved across species implicates EVs as novel mediators of the pathophysiology of HIV. It could help explain the biological effects that HIV has on CD4-negative cells and EVs could become biomarkers of disease progression.