Induction of HIF-1α by HIV-1 Infection in CD4(+) T Cells Promotes Viral Replication and Drives Extracellular Vesicle-Mediated Inflammation.
Induction of HIF-1α by HIV-1 Infection in CD4(+) T Cells Promotes Viral Replication and Drives Extracellular Vesicle-Mediated Inflammation.
复制标题
DOI：
10.1128/mbio.00757-18
复制
发表时间：
2018-09-11
期刊：
影响因子：
6.4
通讯作者：
Ostrowski M
中科院分区：
文献类型：
--
作者：
Duette G;Pereyra Gerber P;Rubione J;Perez PS;Landay AL;Crowe SM;Liao Z;Witwer KW;Holgado MP;Salido J;Geffner J;Sued O;Palmer CS;Ostrowski M
人类免疫缺陷病毒1型（HIV-1）是一种非常重要的全球性病原体，它优先靶向CD 4 + T细胞，如果不治疗，会导致获得性免疫缺陷综合征（AIDS）。虽然抗逆转录病毒治疗有效地抑制了病毒血症，但HIV-1感染患者的免疫激活和炎症标志物仍然高于未感染者。缺氧诱导因子1α（hypoxia-inducible factor 1α，HIF-1α）是一种在调节细胞代谢和功能中起重要作用的转录因子。在这里，我们表明，HIV-1感染诱导HIF-1α的活性，这种转录因子维持HIV-1的复制。此外，我们证明了HIF-1α通过促进细胞外囊泡的释放在HIV-1相关炎症中起关键作用，细胞外囊泡的释放反过来触发未感染的旁观者淋巴细胞和巨噬细胞分泌炎症介质。总之，我们确定HIF-1α和细胞外囊泡的协调作用促进病毒复制和炎症，从而有助于HIV-1的发病机制。慢性免疫激活和炎症是HIV-1感染的标志，也是接受抗逆转录病毒治疗（ART）的HIV-1感染者发生严重非AIDS事件的主要原因。在此，我们发现，在HIV-1复制周期中，感染的CD 4 + T细胞中产生的胞质双链DNA（dsDNA）促进了转录因子缺氧诱导因子1α（HIF-1α）的线粒体活性氧（ROS）依赖性稳定，这反过来又增强了病毒复制。此外，我们发现诱导HIF-1α促进细胞外囊泡（EV）的释放。这些EV通过诱导旁观者CD 4 + T细胞分泌γ干扰素以及旁观者巨噬细胞通过HIF-1α依赖性途径分泌白细胞介素6（IL-6）和IL-1β来促进炎症。值得注意的是，从HIV-1感染者的血浆样本中获得的EV也诱导了HIF-1α活性和炎症。总体而言，这项研究表明，HIF-1α通过促进病毒复制和EV释放在HIV-1发病机制中起着至关重要的作用，这些EV协调淋巴细胞和巨噬细胞介导的炎症反应。
Human immunodeficiency virus type 1 (HIV-1) is a very important global pathogen that preferentially targets CD4+ T cells and causes acquired immunodeficiency syndrome (AIDS) if left untreated. Although antiretroviral treatment efficiently suppresses viremia, markers of immune activation and inflammation remain higher in HIV-1-infected patients than in uninfected individuals. The hypoxia-inducible factor 1α (HIF-1α) is a transcription factor that plays a fundamental role in coordinating cellular metabolism and function. Here we show that HIV-1 infection induces HIF-1α activity and that this transcription factor upholds HIV-1 replication. Moreover, we demonstrate that HIF-1α plays a key role in HIV-1-associated inflammation by promoting the release of extracellular vesicles which, in turn, trigger the secretion of inflammatory mediators by noninfected bystander lymphocytes and macrophages. In summary, we identify that the coordinated actions of HIF-1α and extracellular vesicles promote viral replication and inflammation, thus contributing to HIV-1 pathogenesis. Chronic immune activation and inflammation are hallmarks of HIV-1 infection and a major cause of serious non-AIDS events in HIV-1-infected individuals on antiretroviral treatment (ART). Herein, we show that cytosolic double-stranded DNA (dsDNA) generated in infected CD4+ T cells during the HIV-1 replication cycle promotes the mitochondrial reactive oxygen species (ROS)-dependent stabilization of the transcription factor hypoxia-inducible factor 1α (HIF-1α), which in turn, enhances viral replication. Furthermore, we show that induction of HIF-1α promotes the release of extracellular vesicles (EVs). These EVs foster inflammation by inducing the secretion of gamma interferon by bystander CD4+ T cells and secretion of interleukin 6 (IL-6) and IL-1β by bystander macrophages through an HIF-1α-dependent pathway. Remarkably, EVs obtained from plasma samples from HIV-1-infected individuals also induced HIF-1α activity and inflammation. Overall, this study demonstrates that HIF-1α plays a crucial role in HIV-1 pathogenesis by promoting viral replication and the release of EVs that orchestrate lymphocyte- and macrophage-mediated inflammatory responses.