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

RUBIONE, JULIA; CROWE, SUZANNE M.; HOLGADO, MARÍA PÍA; PEREYRA GERBER, PEHUEN; SUED, OMAR; LANDAY, ALAN L.; DUETTE, GABRIEL; WITWER, KENNETH W.; PEREZ, PAULA S.; GEFFNER, JORGE; LIAO, ZHAOHAO; OSTROWSKI, MATIAS; SALIDO, JIMENA; RUBIONE, JULIA; PALMER, CLOVIS S.; CROWE, SUZANNE M.; HOLGADO, MARÍA PÍA; SUED, OMAR; DUETTE, GABRIEL; PEREZ, PAULA S.; LIAO, ZHAOHAO; SALIDO, JIMENA; PALMER, CLOVIS S.; PEREYRA GERBER, PEHUEN; LANDAY, ALAN L.; WITWER, KENNETH W.; GEFFNER, JORGE; OSTROWSKI, MATIAS

mBio

American Society for Microbiology

Lugar: Washington; Año: 2018 vol. 9

2161-2129

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 1 (HIF-1), which in turn, enhances viral replication. Furthermore, we show that induction of HIF-1 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-1 by bystander macrophages through an HIF-1-dependent pathway. Remarkably, EVs obtained from plasma samples from HIV-1-infected individuals also induced HIF-1 activity and inflammation. Overall, this study demonstrates that HIF-1 plays a crucial role in HIV-1 pathogenesis by promoting viral replication and the release of EVs that orchestrate lymphocyte- and macrophagemediated inflammatory responses.