INDUCTION OF HIF-1Α BY HIV-1 INFECTION IN CD4 T CELLS PROMOTES VIRAL REPLICATION AND DRIVES EXTRACELLULAR VESICLE MEDIATED INFLAMMATION

DUETTE, GABRIEL; RUBIONE, JULIA; PEREYRA GERBER, PEHUEN; PEREZ, PAULA S.; ADAMCZYK, ALAN; ROMANIUK, ALBERTINA; GEFFNER, JORGE; PALMER, CLOVIS; OSTROWSKI, MATIAS

Mar del Plata

Congreso; LXIV Reunión anual de la Sociedad Argentina de Inmunología; 2018

Sociedad Argentina de Inmunología

Background: Human Immunodeficiency Virus type 1 (HIV-1) is avery important global pathogen that preferentially targets CD4+ Tcells and causes Acquired Immunodeficiency Syndrome (AIDS) ifleft untreated. Although antiretroviral treatment efficiently suppresses viremia, markers of immune activation and inflammation remainelevated in HIV-1 infected patients. Our aim was to analyze whetherHIF-1α (a transcription factor that coordinates cellular metabolismand immune functions) and Extracellular Vesicles (EVs), play a rolein HIV-1 associated inflammation.Methods: CD4+T cells isolated from the blood of healthy donorswere activated with anti-CD3/CD28 antibodies and infected in vitro with HIV-1. Then, EVs purified by differential centrifugation wereadded to non-infected CD4+T cells and macrophages. Supernatantswere harvested 24 h later and cytokine production was evaluatedby CBA kit. To evaluate the role of mitochondrial ROS (mROS) andHIF-1α signaling in the production of proinflammatory EVs, we usedthe pharmacological inhibitors MitoTEMPO(500μM) and Equinomycin(1nM) respectively. HIV-1 replication was evaluated measuringp24 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-1α (HIF-1α), which in turn, enhances viral replication(p