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Tetherin Antagonism by HIV-1 Group M Nef Proteins.

Tetherin Antagonism by HIV-1 Group M Nef Proteins.
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Arias JF, Colomer-Lluch M, von Bredow B, Greene JM, MacDonald J, O'Connor DH, Serra-Moreno R, Evans DT,


Arias JF, Colomer-Lluch M, von Bredow B, Greene JM, MacDonald J, O'Connor DH, Serra-Moreno R, Evans DT, (click to view)

Arias JF, Colomer-Lluch M, von Bredow B, Greene JM, MacDonald J, O'Connor DH, Serra-Moreno R, Evans DT,

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Journal of virology 2016 9 21() pii

Abstract

Although Nef is the viral gene product used by most simian immunodeficiency viruses to overcome restriction by tetherin, this activity was acquired by the Vpu protein of HIV-1 group M viruses due to the absence of sequences in human tetherin that confer susceptibility to Nef. Thus, it is widely accepted that HIV-1 group M uses Vpu instead of Nef to counteract tetherin. Challenging this paradigm, we identified Nef alleles of HIV-1 group M isolates with significant activity against human tetherin. These Nef proteins promoted virus release and tetherin downmodulation from the cell surface, and in the context of vpu-deleted HIV-1 recombinants, enhanced virus replication and resistance to antibody-dependent cell-mediated cytotoxicity (ADCC). Further analysis revealed that the Vpu proteins from several of these viruses lack anti-tetherin activity, suggesting that under certain circumstances, HIV-1 group M Nef may acquire the ability to counteract tetherin to compensate for the loss of this function by Vpu. These observations illustrate the remarkable plasticity of HIV-1 in overcoming restriction by tetherin and challenge the prevailing view that all HIV-1 group M isolates use Vpu to counteract tetherin.

IMPORTANCE
Most HIV-1 group M viruses, the main group of HIV-1 responsible for the global AIDS pandemic, use their Vpu proteins to overcome restriction by tetherin (BST-2 or CD317), which is a transmembrane protein that inhibits virus release from infected cells. Here we show that the Nef proteins of certain HIV-1 group M isolates can acquire the ability to counteract tetherin. These results challenge the current paradigm that HIV-1 group M exclusively uses Vpu to counteract tetherin and underscore the importance of tetherin antagonism for efficient viral replication.

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