Novel Mechanism of Microvesicle Regulation by the Antiviral Protein Tetherin During HIV Infection.
Loading...
Issue Date
2020-09
Authors
Weber, Emily A
Singh, Meera V
Singh, Vir B
Jackson, Joseph W
Ture, Sara K
Suwunnakorn, Sumanun
Morrell, Craig N
Maggirwar, Sanjay B
Degree
Advisor
Committee Members
Journal Title
Journal ISSN
Volume Title
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.
Citation
Weber EA, Singh MV, Singh VB, Jackson JW, Ture SK, Suwunnakorn S, Morrell CN, Maggirwar SB. Novel Mechanism of Microvesicle Regulation by the Antiviral Protein Tetherin During HIV Infection. J Am Heart Assoc. 2020 Sep;9(17):e015998. doi: 10.1161/JAHA.120.015998. Epub 2020 Aug 21. PMID: 32819189; PMCID: PMC7660781.
ACPHS Research Commons URI
Description
Grants
R01 HL123346/HL/NHLBI NIH HHS/United States , R01 NS066801/NS/NINDS NIH HHS/United States , P30 AI078498/AI/NIAID NIH HHS/United States , T32 AI049815/AI/NIAID NIH HHS/United States