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

Abstract

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.

Mycobacterium tuberculosis Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics

“…Importantly, levels of estrogen signaling proteins involved in induction of mitochondrial ROS and HIV-1 reactivation are enriched in M. tuberculosis exosomes (66,67). HIF-1 signaling plays an important role in HIV-1 pathogenesis by facilitating viral replication and promoting lymphocyte and macrophage-mediated inflammatory responses (68). HIF-1 pathway proteins are specifically induced in M. tuberculosis exosomes (Fig.…”

HIF-1α Modulates Core Metabolism and Virus Replication in Primary Airway Epithelial Cells Infected with Respiratory Syncytial Virus

“…Several viruses, often associated with chronic infections, such as hepatitis C virus, herpesviruses, human papillomavirus and immunodeficiency virus (HIV), have been shown to induce HIF-1α activation, leading to metabolic cellular reprogramming and promotion of virus replication [ 31 , 34 , 35 ]. Influenza virus infection was also able to induce HIF-1α activation in lung carcinoma and monocytic cell lines; however, a lack of lung epithelial cell expression of HIF-1α in a mouse model of influenza infection was associated with enhanced virus replication [ 36 , 37 ].…”

Mycobacterium tuberculosis reactivates HIV via exosomes mediated resetting of cellular redox potential and bioenergetics

“…Importantly, estrogen signaling proteins involved in induction of mitochondrial ROS and HIV-1 reactivation are enriched in Mtb -exosomes [66, 67]. HIF-1 signaling plays an important role in HIV-1 pathogenesis by facilitating viral replication and promoting lymphocyte and macrophage mediated inflammatory response [68]. HIF-1 pathway proteins are specifically induced in Mtb exosomes (Fig.…”