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Tetherin/BST-2: Restriction Factor or Immunomodulator?

[ Vol. 14 , Issue. 3 ]

Author(s):

Sam X. Li, Bradley S. Barrett, Kejun Guo and Mario L. Santiago   Pages 235 - 246 ( 12 )

Abstract:


Background: Cell-mediated immune (CMI) responses are critical for the control of HIV-1 infection and their importance was highlighted by the existence of viral proteins, particularly Vpu and Nef, that antagonize these responses. Pandemic HIV-1 Vpu counteracts Tetherin/BST-2, a host factor that could prevent the release of HIV-1 virions by tethering virions on the cell surface, but a link between Tetherin and HIV-1 CMI responses has not yet been demonstrated in vivo. In vitro, the virological and immunological impact of Tetherin-mediated accumulation of virions ranged from enhanced or diminished cell-to-cell spread to enhanced recognition by virus-specific antibodies for natural killer cellmediated lysis. However, Tetherin-restricted virions could be internalized through an endocytosis motif in the Tetherin cytoplasmic tail. Methods: Given the uncertainties on which in vitro results manifest in vivo and the dearth of knowledge on how Tetherin influences retroviral immunity, in vivo retrovirus infections in mice encoding wild-type, null and endocytosis-defective Tetherin were performed. Here, we review and highlight the results from these in vivo studies. Results: Current data suggests that endocytosis-defective Tetherin functions as a potent innate restriction factor. By contrast, endocytosis-competent Tetherin, the form found in most mammals including humans and the form counteracted by HIV-1 Vpu, was linked to stronger CMI responses in mice. Conclusion: We propose that the main role of endocytosis-competent Tetherin is not to directly restrict retroviral replication, but to promote a more effective CMI response against retroviruses.

Keywords:

HIV-1, cell-mediated immunity, tetherin, BST-2, Vpu, Nef, dendritic cell, retrovirus.

Affiliation:

Division of Infectious Diseases, University of Colorado Denver, Mail Stop B-168, 12700 E 19th Avenue, Aurora, CO 80045, USA

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