Exosomes from uninfected cells activate transcription of latent HIV-1
Exosomes from uninfected cells activate transcription of latent HIV-1
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DOI：
10.1074/jbc.m117.793521
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发表时间：
2017-07-14
影响因子：
4.8
通讯作者：
Kashanchi, Fatah
中科院分区：
文献类型：
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作者：
Barclay, Robert A.;Schwab, Angela;Kashanchi, Fatah
HIV-1感染导致艾滋病，感染全世界数百万人。由于其潜伏能力，该病毒可以持续存在于慢性感染状态。我们以前已经证明了HIV-1感染和外泌体产生之间的联系。具体来说，我们已经报道了外泌体将病毒蛋白和RNA从感染细胞转运到邻近的未感染细胞。然后，这些病毒产物可以引发先天性免疫应答，导致Toll样受体和NF-κ B途径的激活。在这项研究中，我们询问来自未感染细胞的外泌体是否可以激活感染细胞中的潜伏HIV-1。我们观察到，无论联合抗逆转录病毒治疗，在暴露于未感染细胞纯化的外泌体的野生型HIV-1感染细胞中，短长度和长长度病毒转录物均增加。对这一发现的可能机制的研究表明，外泌体增加了感染细胞中HIV-1启动子上的RNA聚合酶II。这些病毒转录物，包括反式激活反应（TAR）RNA和一种新的RNA，我们称之为TAR-gag，然后可以被包装到外泌体中，并可能被输出到邻近的未感染细胞，导致细胞活化增加。为了更好地破译所涉及的外泌体释放途径，我们使用siRNA来抑制ESCRT（转运所需的内体分选复合物）蛋白的表达，并发现ESCRT II和IV显著控制外泌体释放。总的来说，这些结果意味着来自未感染细胞的外泌体激活感染细胞中的潜伏HIV-1，并且在体内可能不存在真正的转录潜伏期，特别是在存在联合抗逆转录病毒疗法的情况下。
HIV-1 infection causes AIDS, infecting millions worldwide. The virus can persist in a state of chronic infection due to its ability to become latent. We have previously shown a link between HIV-1 infection and exosome production. Specifically, we have reported that exosomes transport viral proteins and RNA from infected cells to neighboring uninfected cells. These viral products could then elicit an innate immune response, leading to activation of the Toll-like receptor and NF-kappa B pathways. In this study, we asked whether exosomes from uninfected cells could activate latent HIV-1 in infected cells. We observed that irrespective of combination antiretroviral therapy, both short-and long-length viral transcripts were increased in wildtype HIV-1-infected cells exposed to purified exosomes from uninfected cells. A search for a possible mechanism for this finding revealed that the exosomes increase RNA polymerase II loading onto the HIV-1 promoter in the infected cells. These viral transcripts, which include trans-activation response (TAR) RNA and a novel RNA that we termed TAR-gag, can then be packaged into exosomes and potentially be exported to neighboring uninfected cells, leading to increased cellular activation. To better decipher the exosome release pathways involved, we used siRNA to suppress expression of ESCRT (endosomal sorting complex required for transport) proteins and found that ESCRT II and IV significantly control exosome release. Collectively, these results imply that exosomes from uninfected cells activate latent HIV-1 in infected cells and that true transcriptional latency may not be possible in vivo, especially in the presence of combination antiretroviral therapy.