Vpu enhances retrovirus particle release from the plasma membrane at a stage following classical particle budding. Vpu inhibits a potent cellular restriction to release that was identified in 2008 as BST2 or tetherin. The overall goals of this project are to define the mechanism of restriction of particle release by tetherin, and the mechanism by which Vpu overcomes tetherin-mediated restriction. Recycling pathways, the actin-associated cytoskeleton, and the role of tetherin in HIV-infected macrophages are specific areas of focus in this project. Experiments in Aim 1 will define the role of cellular recycling pathways on tetherin-mediated restriction of particle release. Dominant-negative inhibitors of specific steps in endocytic trafficking and recycling will be employed to dissect the trafficking of tetherin and correlate this with restriction. Experiments in Aim 2 examine the role of tetherin in HIV-infected human macrophages. The potential role of tetherin in forming the HIV particle-enriched intracellular compartment in macrophages will be addressed.
In Aim 3, the role of RICH2, Ezrin, and the actin-associated cytoskeleton in tetherin-mediated restriction will be examined. The role of the coiled-coil domain on the extracellular portion of tetherin will be analyzed using a null mutant. Together, these studies will provide important new information related to the cellular biology of tetherin and the paths through which Vpu acts to overcome tetherin-mediated retention of viral particles.

Public Health Relevance

This project is relevant to public health because it will tell us how the HIV protein Vpu works to enhance the growth of the virus. Vpu interacts with components of the human cell to disrupt the effects of a cell protein called tetherin. This project could reveal new ways to inhibit this aspect of HIV, resulting in new drugs against HIV and potentially against other harmful viruses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI058828-08
Application #
8389640
Study Section
Special Emphasis Panel (ZRG1-AARR-K (02))
Program Officer
Sharma, Opendra K
Project Start
2003-12-01
Project End
2015-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
8
Fiscal Year
2013
Total Cost
$364,250
Indirect Cost
$129,250
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Hammonds, Jason; Ding, Lingmei; Chu, Hin et al. (2012) The tetherin/BST-2 coiled-coil ectodomain mediates plasma membrane microdomain localization and restriction of particle release. J Virol 86:2259-72
Ali, Mohammed S; Hammonds, Jason; Ding, Lingmei et al. (2010) CAML does not modulate tetherin-mediated restriction of HIV-1 particle release. PLoS One 5:e9005
Hammonds, Jason; Wang, Jaang-Jiun; Yi, Hong et al. (2010) Immunoelectron microscopic evidence for Tetherin/BST2 as the physical bridge between HIV-1 virions and the plasma membrane. PLoS Pathog 6:e1000749
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