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 #
5R01AI058828-07
Application #
8196960
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
2011-12-01
Budget End
2012-11-30
Support Year
7
Fiscal Year
2012
Total Cost
$387,500
Indirect Cost
$137,500
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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Strauss, Joshua D; Hammonds, Jason E; Yi, Hong et al. (2015) Three-Dimensional Structural Characterization of HIV-1 Tethered to Human Cells. J Virol 90:1507-21
Yi, Hong; Strauss, Joshua D; Ke, Zunlong et al. (2015) Native immunogold labeling of cell surface proteins and viral glycoproteins for cryo-electron microscopy and cryo-electron tomography applications. J Histochem Cytochem 63:780-92
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Kiss, Gabriella; Chen, Xuemin; Brindley, Melinda A et al. (2014) Capturing enveloped viruses on affinity grids for downstream cryo-electron microscopy applications. Microsc Microanal 20:164-74
Wen, Xiaoyun; Ding, Lingmei; Hunter, Eric et al. (2014) An siRNA screen of membrane trafficking genes highlights pathways common to HIV-1 and M-PMV virus assembly and release. PLoS One 9:e106151
Wen, Xiaoyun; Ding, Lingmei; Wang, Jaang-Jiun et al. (2014) ROCK1 and LIM kinase modulate retrovirus particle release and cell-cell transmission events. J Virol 88:6906-21
Chu, Hin; Wang, Jaang-Jiun; Qi, Mingli et al. (2012) The intracellular virus-containing compartments in primary human macrophages are largely inaccessible to antibodies and small molecules. PLoS One 7:e35297
Hammonds, Jason; Wang, Jaang-Jiun; Spearman, Paul (2012) Restriction of Retroviral Replication by Tetherin/BST-2. Mol Biol Int 2012:424768
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

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