HIV-1 Vpu antagonism of tetherin inhibits antibody-dependent cellular cytotoxic responses by natural killer cells

The type I interferon-inducible factor tetherin retains virus particles on the surfaces of cells infected with vpu-deficient human immunodeficiency virus type 1 (HIV-1). While this mechanism inhibits cell-free viral spread, the immunological implications of tethered virus have not been investigated....

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Bibliographic Details
Published in:Journal of virology 2014-06, Vol.88 (11), p.6031-6046
Main Authors: Alvarez, Raymond A, Hamlin, Rebecca E, Monroe, Anthony, Moldt, Brian, Hotta, Mathew T, Rodriguez Caprio, Gabriela, Fierer, Daniel S, Simon, Viviana, Chen, Benjamin K
Format: Article
Language:English
Subjects:
Antibody-Dependent Cell Cytotoxicity - immunology
Antigens, CD - immunology
CD4-Positive T-Lymphocytes - immunology
CD4-Positive T-Lymphocytes - virology
Flow Cytometry
GPI-Linked Proteins - antagonists & inhibitors
GPI-Linked Proteins - immunology
Human immunodeficiency virus
Human immunodeficiency virus 1
Human Immunodeficiency Virus Proteins - immunology
Humans
Jurkat Cells
Killer Cells, Natural - immunology
Lysosomal-Associated Membrane Protein 1 - immunology
Opsonin Proteins - immunology
Pathogenesis and Immunity
Receptors, IgG - immunology
Receptors, IgG - metabolism
Signal Transduction - immunology
Viral Regulatory and Accessory Proteins - immunology
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Summary:The type I interferon-inducible factor tetherin retains virus particles on the surfaces of cells infected with vpu-deficient human immunodeficiency virus type 1 (HIV-1). While this mechanism inhibits cell-free viral spread, the immunological implications of tethered virus have not been investigated. We found that surface tetherin expression increased the antibody opsonization of vpu-deficient HIV-infected cells. The absence of Vpu also stimulated NK cell-activating FcγRIIIa signaling and enhanced NK cell degranulation and NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). The deletion of vpu in HIV-1-infected primary CD4(+) T cells enhanced the levels of antibody binding and Fc receptor signaling mediated by HIV-positive-patient-derived antibodies. The magnitudes of antibody binding and Fc signaling were both highly correlated to the levels of tetherin on the surfaces of infected primary CD4 T cells. The affinity of antibody binding to FcγRIIIa was also found to be critical in mediating efficient Fc activation. These studies implicate Vpu antagonism of tetherin as an ADCC evasion mechanism that prevents antibody-mediated clearance of virally infected cells. The ability of the HIV-1 accessory factor to antagonize tetherin has been considered to primarily function by limiting the spread of virus by preventing the release of cell-free virus. This study supports the hypothesis that a major function of Vpu is to decrease the recognition of infected cells by anti-HIV antibodies at the cell surface, thereby reducing recognition by antibody-dependent clearance by natural killer cells.
ISSN:0022-538X
1098-5514
DOI:10.1128/jvi.00449-14