Publications & Reports

Induction of HIF-1alpha by HIV-1 Infection in CD4(+) T Cells Promotes Viral Replication and Drives Extracellular Vesicle-Mediated Inflammation.

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
INBIRS, Facultad de Medicina, Buenos Aires, Argentina.

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 1alpha (HIF-1alpha), which in turn, enhances viral replication. Furthermore, we show that induction of HIF-1alpha 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-1beta by bystander macrophages through an HIF-1alpha-dependent pathway. Remarkably, EVs obtained from plasma samples from HIV-1-infected individuals also induced HIF-1alpha activity and inflammation. Overall, this study demonstrates that HIF-1alpha 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 1alpha (HIF-1alpha) is a transcription factor that plays a fundamental role in coordinating cellular metabolism and function. Here we show that HIV-1 infection induces HIF-1alpha activity and that this transcription factor upholds HIV-1 replication. Moreover, we demonstrate that HIF-1alpha 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-1alpha and extracellular vesicles promote viral replication and inflammation, thus contributing to HIV-1 pathogenesis.

Link to publisher’s web site

Publication

  • Journal: mBio
  • Published: 11/09/2018
  • Volume: 9
  • Issue: 5

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