INBIRS, Facultad de Medicina, Buenos Aires, Argentina.
Department of Immunology-Microbiology, Rush University Medical Center, Chicago, Illinois, USA.
mBio. 2018 Sep 11;9(5):e00757-18. doi: 10.1128/mBio.00757-18.
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. 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.
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 感染者发生严重非艾滋病事件的主要原因。在此，我们表明，在 HIV-1 复制周期中，感染的 CD4 T 细胞中产生的细胞质双链 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，进而增强了病毒复制。此外，我们表明，HIF-1α 的诱导促进了细胞外囊泡（EVs）的释放。这些 EV 通过诱导旁观者 CD4 T 细胞分泌γ干扰素以及旁观者巨噬细胞分泌白细胞介素 6（IL-6）和白细胞介素 1β（IL-1β），通过 HIF-1α 依赖性途径促进炎症。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释放细胞外囊泡来协调淋巴细胞和巨噬细胞介导的炎症反应，在 HIV-1 发病机制中发挥着至关重要的作用。
人类免疫缺陷病毒 1（HIV-1）是一种非常重要的全球病原体，它优先靶向 CD4 T 细胞，如果不治疗，会导致获得性免疫缺陷综合征（AIDS）。尽管抗逆转录病毒治疗能有效地抑制病毒血症，但 HIV-1 感染者的免疫激活和炎症标志物仍高于未感染者。缺氧诱导因子 1α（HIF-1α）是一种转录因子，在协调细胞代谢和功能方面发挥着重要作用。在这里，我们表明 HIV-1 感染诱导了 HIF-1α 的活性，而这种转录因子维持了 HIV-1 的复制。此外，我们证明 HIF-1α 通过促进细胞外囊泡的释放在 HIV-1 相关炎症中发挥关键作用，而这些细胞外囊泡反过来又触发非感染的旁观者淋巴细胞和巨噬细胞分泌炎症介质。总之，我们发现 HIF-1α 和细胞外囊泡的协同作用促进了病毒复制和炎症，从而促进了 HIV-1 的发病机制。
