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Journal of Virology, November 2009, p. 11966-11978, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01515-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Antagonism to and Intracellular Sequestration of Human Tetherin by the Human Immunodeficiency Virus Type 2 Envelope Glycoprotein{triangledown}

Anna Le Tortorec and Stuart J. D. Neil*

Department of Infectious Disease, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, United Kingdom

Received 21 July 2009/ Accepted 2 September 2009

Tetherin (CD317/BST-2), an interferon-induced membrane protein, restricts the release of nascent retroviral particles from infected cell surfaces. While human immunodeficiency virus type 1 (HIV-1) encodes the accessory gene vpu to overcome the action of tetherin, the lineage of primate lentiviruses that gave rise to HIV-2 does not. It has been previously reported that the HIV-2 envelope glycoprotein has a Vpu-like function in promoting virus release. Here we demonstrate that the HIV-2 Rod envelope glycoprotein (HIV-2 Rod Env) is a tetherin antagonist. Expression of HIV-2 Rod Env, but not that of HIV-1 or the closely related simian immunodeficiency virus (SIV) SIVmac1A11, counteracts tetherin-mediated restriction of Vpu-defective HIV-1 in a cell-type-specific manner. This correlates with the ability of the HIV-2 Rod Env to mediate cell surface downregulation of tetherin. Antagonism requires an endocytic motif conserved across HIV/SIV lineages in the gp41 cytoplasmic tail, but specificity for tetherin is governed by extracellular determinants in the mature Env protein. Coimmunoprecipitation studies suggest an interaction between HIV-2 Rod Env and tetherin, but unlike studies with Vpu, we found no evidence of tetherin degradation. In the presence of HIV-2 Rod Env, tetherin localization is restricted to the trans-Golgi network, suggesting Env-mediated effects on tetherin trafficking sequester it from virus assembly sites on the plasma membrane. Finally, we recapitulated these observations in HIV-2-infected CD4+ T-cell lines, demonstrating that tetherin antagonism and sequestration occur at physiological levels of Env expression during virus replication.

* Corresponding author. Mailing address: Dept. Infectious Disease, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, United Kingdom. Phone: 44 207 188 8279. Fax: 44 207 188 3085. E-mail: stuart.neil{at}kcl.ac.uk

{triangledown} Published ahead of print on 9 September 2009.

Journal of Virology, November 2009, p. 11966-11978, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01515-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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