Induction of HIF-1α by HIV-1 Infection in CD4<sup>+</sup> T Cells Promotes Viral Replication and Drives Extracellular Vesicle-Mediated Inflammation
ABSTRACT 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...
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American Society for Microbiology
2018
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oai:doaj.org-article:eb1accfedd334fa5b0ed56cc2700e7cd2021-11-15T15:58:20ZInduction of HIF-1α by HIV-1 Infection in CD4<sup>+</sup> T Cells Promotes Viral Replication and Drives Extracellular Vesicle-Mediated Inflammation10.1128/mBio.00757-182150-7511https://doaj.org/article/eb1accfedd334fa5b0ed56cc2700e7cd2018-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00757-18https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE 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.Gabriel DuettePehuen Pereyra GerberJulia RubionePaula S. PerezAlan L. LandaySuzanne M. CroweZhaohao LiaoKenneth W. WitwerMaría Pía HolgadoJimena SalidoJorge GeffnerOmar SuedClovis S. PalmerMatias OstrowskiAmerican Society for MicrobiologyarticleCD4+ T lymphocyteextracellular vesicleshypoxia-inducible factor 1 alphainflammationhuman immunodeficiency virusmacrophageMicrobiologyQR1-502ENmBio, Vol 9, Iss 5 (2018) |
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| collection |
DOAJ |
| language |
EN |
| topic |
CD4+ T lymphocyte extracellular vesicles hypoxia-inducible factor 1 alpha inflammation human immunodeficiency virus macrophage Microbiology QR1-502 |
| spellingShingle |
CD4+ T lymphocyte extracellular vesicles hypoxia-inducible factor 1 alpha inflammation human immunodeficiency virus macrophage Microbiology QR1-502 Gabriel Duette Pehuen Pereyra Gerber Julia Rubione Paula S. Perez Alan L. Landay Suzanne M. Crowe Zhaohao Liao Kenneth W. Witwer María Pía Holgado Jimena Salido Jorge Geffner Omar Sued Clovis S. Palmer Matias Ostrowski Induction of HIF-1α by HIV-1 Infection in CD4<sup>+</sup> T Cells Promotes Viral Replication and Drives Extracellular Vesicle-Mediated Inflammation |
| description |
ABSTRACT 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. IMPORTANCE 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. |
| format |
article |
| author |
Gabriel Duette Pehuen Pereyra Gerber Julia Rubione Paula S. Perez Alan L. Landay Suzanne M. Crowe Zhaohao Liao Kenneth W. Witwer María Pía Holgado Jimena Salido Jorge Geffner Omar Sued Clovis S. Palmer Matias Ostrowski |
| author_facet |
Gabriel Duette Pehuen Pereyra Gerber Julia Rubione Paula S. Perez Alan L. Landay Suzanne M. Crowe Zhaohao Liao Kenneth W. Witwer María Pía Holgado Jimena Salido Jorge Geffner Omar Sued Clovis S. Palmer Matias Ostrowski |
| author_sort |
Gabriel Duette |
| title |
Induction of HIF-1α by HIV-1 Infection in CD4<sup>+</sup> T Cells Promotes Viral Replication and Drives Extracellular Vesicle-Mediated Inflammation |
| title_short |
Induction of HIF-1α by HIV-1 Infection in CD4<sup>+</sup> T Cells Promotes Viral Replication and Drives Extracellular Vesicle-Mediated Inflammation |
| title_full |
Induction of HIF-1α by HIV-1 Infection in CD4<sup>+</sup> T Cells Promotes Viral Replication and Drives Extracellular Vesicle-Mediated Inflammation |
| title_fullStr |
Induction of HIF-1α by HIV-1 Infection in CD4<sup>+</sup> T Cells Promotes Viral Replication and Drives Extracellular Vesicle-Mediated Inflammation |
| title_full_unstemmed |
Induction of HIF-1α by HIV-1 Infection in CD4<sup>+</sup> T Cells Promotes Viral Replication and Drives Extracellular Vesicle-Mediated Inflammation |
| title_sort |
induction of hif-1α by hiv-1 infection in cd4<sup>+</sup> t cells promotes viral replication and drives extracellular vesicle-mediated inflammation |
| publisher |
American Society for Microbiology |
| publishDate |
2018 |
| url |
https://doaj.org/article/eb1accfedd334fa5b0ed56cc2700e7cd |
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