title: Tetherin Antagonism by HIV-1 Group M Nef Proteins.
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 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 ofvpu-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 antitetherin 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.IMPORTANCEMost viruses of HIV-1 group M, 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Arias
authors.affiliation: Department of Biological Sciences, College of Arts and Sciences, Texas Tech University, Lubbock, Texas, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Colomer-Lluch
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: von Bredow
authors.affiliation: Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Greene
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: MacDonald
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.|Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: O'Connor
authors.affiliation: Department of Biological Sciences, College of Arts and Sciences, Texas Tech University, Lubbock, Texas, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Serra-Moreno
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA dtevans2@wisc.edu.|Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Evans