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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI081668-02S1
Application #
8074700
Study Section
Special Emphasis Panel (ZRG1-AARR-A (02))
Program Officer
Sharma, Opendra K
Project Start
2010-06-01
Project End
2011-07-31
Budget Start
2010-06-01
Budget End
2011-07-31
Support Year
2
Fiscal Year
2010
Total Cost
$86,776
Indirect Cost
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
933863508
City
San Diego
State
CA
Country
United States
Zip Code
92161
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