HIV-1 Vpu enhances the release of virions from infected cells by overcoming a cellular inhibitor that retains nascent virions within and on infected cells. The identity of this inhibitor has recently been revealed: it is the transmembrane, GPI-anchored protein BST-2, also known as HM1.24, CD317, or """"""""tetherin."""""""" BST-2 seems able to affect diverse enveloped virions, suggesting a broad role in the host defense against viruses including HIV-1. The research proposed here has three specific aims: 1) to reveal how BST-2 retains HIV-1 virions on infected cells;2) to determine how Vpu antagonizes this restriction;3) to understand the regulation of BST-2 during the innate immune response and to explore the potential function of BST-2 in antigen presenting cells.
These aims will be pursued using a concerted experimental approach including targeted mutagenesis of BST-2 and Vpu, characterization of the interaction between BST-2 and Vpu, analysis of the effects of Vpu on the intracellular trafficking and virion-incorporation of BST-2, and analysis of the regulation and function of BST-2 in primary T lymphocytes and antigen presenting cells. When these aims are completed, we will know how BST-2 retains virions on infected cells, how Vpu counteracts this protein, how BST-2 is regulated during the innate immune response, and whether it plays a role in the uptake of virions by antigen presenting cells during the adaptive immune response.
BST-2 is a newly identified host-cell protein that retains virus particles including those of HIV-1 on infected cells. The HIV-1 protein Vpu counteracts this host defense. This research is designed to explore how BST-2 retains virus particles, how Vpu antagonizes this activity, and how BST-2 is regulated within primary cells of the immune system.
|Ball, K Aurelia; Johnson, Jeffrey R; Lewinski, Mary K et al. (2016) Non-degradative Ubiquitination of Protein Kinases. PLoS Comput Biol 12:e1004898|
|Tokarev, Andrey; Stoneham, Charlotte; Lewinski, Mary K et al. (2015) Pharmacologic Inhibition of Nedd8 Activation Enzyme Exposes CD4-Induced Epitopes within Env on Cells Expressing HIV-1. J Virol 90:2486-502|
|Abdel-Mohsen, Mohamed; Deng, Xutao; Liegler, Teri et al. (2014) Effects of alpha interferon treatment on intrinsic anti-HIV-1 immunity in vivo. J Virol 88:763-7|
|Jafari, Moein; Guatelli, John; Lewinski, Mary K (2014) Activities of transmitted/founder and chronic clade B HIV-1 Vpu and a C-terminal polymorphism specifically affecting virion release. J Virol 88:5062-78|
|Jia, Xiaofei; Weber, Erin; Tokarev, Andrey et al. (2014) Structural basis of HIV-1 Vpu-mediated BST2 antagonism via hijacking of the clathrin adaptor protein complex 1. Elife 3:e02362|
|Tokarev, Andrey; Suarez, Marissa; Kwan, Wilson et al. (2013) Stimulation of NF-?B activity by the HIV restriction factor BST2. J Virol 87:2046-57|
|Miyakawa, Kei; Sawasaki, Tatsuya; Matsunaga, Satoko et al. (2012) Interferon-induced SCYL2 limits release of HIV-1 by triggering PP2A-mediated dephosphorylation of the viral protein Vpu. Sci Signal 5:ra73|
|Pillai, Satish K; Abdel-Mohsen, Mohamed; Guatelli, John et al. (2012) Role of retroviral restriction factors in the interferon-?-mediated suppression of HIV-1 in vivo. Proc Natl Acad Sci U S A 109:3035-40|
|Skasko, Mark; Wang, Yan; Tian, Ye et al. (2012) HIV-1 Vpu protein antagonizes innate restriction factor BST-2 via lipid-embedded helix-helix interactions. J Biol Chem 287:58-67|
|Tokarev, Andrey A; Munguia, Jason; Guatelli, John C (2011) Serine-threonine ubiquitination mediates downregulation of BST-2/tetherin and relief of restricted virion release by HIV-1 Vpu. J Virol 85:51-63|
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