Role of the Ebolavirus Glycoprotein in Countering Tetherin During Viral Budding

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Degree type
Doctor of Philosophy (PhD)
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Cell & Molecular Biology
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bst2
ebolavirus
glycoprotein
tetherin
Microbiology
Molecular Biology
Virology
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2016-11-29T00:00:00-08:00
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Abstract

Ebola virus (EBOV) is the causative agent of Ebola virus hemorrhagic fever and initiates sporadic outbreaks with very high mortality rates of up to 90%. The only viral surface protein on EBOV virions, the EBOV Glycoprotein (GP1,2), is a known antagonist of the intrinsic innate immune effector Tetherin, which prevents release of budded virions by “tethering” them to the cell. Unlike other Tetherin antagonists, GP1,2 does not degrade Tetherin, remove Tetherin from the cell surface, or sequester Tetherin in intracellular compartments. Thus, the mechanism of how GP1,2 counters Tetherin is not well understood. This study utilizes methods in molecular biology and microbiology to focus on the different domains of GP1,2 and understand their role in countering Tetherin. Using VP40 or HIV-1 Gag to produce virus-like particles (VLP), we show that the GP1,2 glycan cap and transmembrane domain are necessary for GP1,2 anti-Tetherin activity. Chimeric proteins containing alternative transmembrane domains in place of the GP1,2 transmembrane domain fail to counteract Tetherin and release VLP. Additionally, using widefield microscopy, alternative transmembrane domains do not change the surface localization of Tetherin and GP1,2, suggesting that surface interactions may not be important for understanding how GP1,2 counters Tetherin. Other observations and experiments suggest an active role for GP1,2 in the formation of viral particles. In conclusion, we propose a model where the GP1,2 transmembrane domain assists in a budding process that does not allow for incorporation of Tetherin into the budding virions. The model suggests that the GP1,2 transmembrane domain functions to avoid Tetherin mediated restriction and to form viral particles independent of VP40 budding.

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Paul F. Bates
Date of degree
2015-01-01
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