Novel Mechanism of Microvesicle Regulation by the Antiviral Protein Tetherin During HIV Infection

Abstract

Background Microvesicles are cell membrane–derived vesicles that have been shown to augment inflammation. Specifically, monocyte‐derived microvesicles (MDMVs), which can express the coagulation protein tissue factor, contribute to thrombus formation and cardiovascular disease. People living with HIV experience higher prevalence of cardiovascular disease and also exhibit increased levels of plasma microvesicles. The process of microvesicle release has striking similarity to budding of enveloped viruses. The surface protein tetherin inhibits viral budding by physically tethering budding virus particles to cells. Hence, we investigated the role of tetherin in regulating the release of MDMVs during HIV infection. Methods and Results The plasma of aviremic HIV‐infected individuals had increased levels of tissue factor + MDMVs, as measured by flow cytometry, and correlated to reduced tetherin expression on monocytes. Superresolution confocal and electron microscopy showed that tetherin localized at the site of budding MDMVs. Mechanistic studies revealed that the exposure of monocytes to HIV‐encoded Tat triggered tetherin loss and subsequent rise in MDMV production. Overexpression of tetherin in monocytes led to morphologic changes in the pseudopodia directly underneath the MDMVs. Further, tetherin knockout mice demonstrated a higher number of circulating MDMVs and less time to bleeding cessation. Conclusions Our studies define a novel regulatory mechanism of MDMV release through tetherin and explore its contribution to the procoagulatory state that is frequently observed in people with HIV. Such insights could lead to improved therapies for individuals infected with HIV and also for those with cardiovascular disease.

Extracellular Microvesicles Released From Brain Endothelial Cells are Detected in Animal Models Of HIV-1 Signifying Unresolved Inflammation

“…While our studies are the first to analyze TJ containing EVs from an animal model of HIV infection, several recent studies have examined EVs from HIV patients (Weber et al 2020 ; Falasca et al 2021 ; Chettimada et al 2020 ; Kodidela et al 2020 ). Although the isolation methods, vesicle of interest (MV vs. exosome) and target analysis for host origin (monocytes, CNS etc.)…”

“…Although the isolation methods, vesicle of interest (MV vs. exosome) and target analysis for host origin (monocytes, CNS etc.) vary between studies, several have found increased EVs in people living with HIV (PLWH) (Weber et al 2020 ; Chettimada et al 2020 ; Kodidela et al 2020 ; Hijmans et al 2019b ). With regards to MVs of an endothelial origin, Hijmans et al found increased endothelial MVs, identified as CD62E + , in HIV + patients on ART compared to healthy individuals (Hijmans et al 2019b ).…”

“…While the exact function of MVs remains unclear, studies have shown that they can contribute to pathology (Candelario and Steindler 2014 ; Anderson et al 2010 ) or serve as a form of intercellular communication (Pegtel et al 2014 ). HIV-1 infection or viroproteins triggers the production of MVs from various cell types, including but not limited to monocytes (Weber et al 2020 ; Kadiu et al 2012 ), microglia (Wu et al 2015 ), platelets (Poveda et al 2020 ), and peripheral ECs (Hijmans et al 2019a ). Furthermore, there is great interest in the possibility that MVs (and the other EV forms) could be used as biosignatures for monitoring HIV related pathogenesis (Weber et al 2020 ; Falasca et al 2021 ; Bazie et al 2021 ; Pulliam et al 2019 ).…”

“…HIV-1 infection or viroproteins triggers the production of MVs from various cell types, including but not limited to monocytes (Weber et al 2020 ; Kadiu et al 2012 ), microglia (Wu et al 2015 ), platelets (Poveda et al 2020 ), and peripheral ECs (Hijmans et al 2019a ). Furthermore, there is great interest in the possibility that MVs (and the other EV forms) could be used as biosignatures for monitoring HIV related pathogenesis (Weber et al 2020 ; Falasca et al 2021 ; Bazie et al 2021 ; Pulliam et al 2019 ). Although studies have shown that HIV-1 promotes MV production from distinct cell populations, limited information is available regarding the cells that form the BBB.…”

Epstein-Barr Virus Lmp1 Enhances Levels of Microvesicle-Associated Pd-L1

“…Caveolin-1 is essential for sorting of selected miRNAs into MVs (13). Both viruses and MVs emerge from the plasma membrane at lipid raft organizing centers indicating a similar form of biogenesis (14). Elevated levels of EVs in tumor microenvironments and within the circulation correlate to a more advanced disease stage in cancers.…”