Induction of hif-1alpha by HIV-1 infection in CD4 T cells promotes viral replication and drives extracellular vesicle mediated inflammation

JULIA RUBIONE; GABRIEL DUETTE; ALAN ADAMCZYK; PAULA PEREZ; MATIAS OSTROWSKI; PEHUEN PEREYRA; JORGE GEFFNER; MARÍA ALBERTINA ROMANIUK

Mar del plata

Congreso; LXVI Reunion Anual de la Sociedad Argentina de Inmunologia; 2018

Sociedad Argentina de inmunologia

Background: Human Immunode􀀔ciency Virus type 1 (HIV-1) is a very important global pathogen that preferentially targets CD4+ T cells and causes Acquired Immunode􀀔ciency Syndrome (AIDS) if left untreated. Although antiretroviral treatment ef􀀔ciently suppresses viremia, markers of immune activation and in􀀮ammation remain elevated in HIV-1 infected patients. Our aim was to analyze whether HIF-1􀀳 (a transcription factor that coordinates cellular metabolism and immune functions) and Extracellular Vesicles (EVs), play a rolein HIV-1 associated in􀀮ammation.Methods: CD4+T cells isolated from the blood of healthy donors were activated with anti-CD3/CD28 antibodies and infected in vitro with HIV-1. Then, EVs puri􀀔ed by differential centrifugation were added to non-infected CD4+T cells and macrophages. Supernatants were harvested 24 h later and cytokine production was evaluated by CBA kit. To evaluate the role of mitochondrial ROS (mROS) andHIF-1􀀳 signaling in the production of proin􀀮ammatory EVs, we used the pharmacological inhibitors MitoTEMPO(500􀀺M) and Equinomycin(1nM) respectively. HIV-1 replication was evaluated measuring p24 expression by FACS and ELISA.Results: We show that cytosolic dsDNA generated in infected CD4+ T cells during the HIV-1 replication cycle promotes the mitochondrialROS-dependent stabilization of the transcription factor Hypoxia Inducible Factor-1􀀳 (HIF-1􀀳), which in turn, enhances viral replication (p