Identification of Residues in the BST-2 TM Domain Important for Antagonism by HIV-1 Vpu Using a Gain-of-Function Approach

Klaus Strebel,Sandra Kao,Takeshi Yoshida

doi:10.3389/fmicb.2011.00035

Klaus Strebel, Sandra Kao + Show 1 more

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https://doi.org/10.3389/fmicb.2011.00035

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Abstract

The HIV-1 Vpu protein enhances the release of viral particles from the cell-surface in a cell-type specific manner. In the absence of Vpu, nascent virions remain tethered to the cell-surface in restricted cell-types. Recently, the human host factor BST-2/CD317/tetherin was found to be responsible for the inhibition of virus release. It was also reported that HIV-1 Vpu can target human BST-2 but is unable to interfere with the function of murine or simian BST-2. We performed a gain-of-function study to determine which of the differences between human and rhesus BST-2 account for the differential sensitivity to Vpu. We transferred human BST-2 sequences into rhesus BST-2 and assessed the resulting chimeras for inhibition of HIV-1 virus release and sensitivity to Vpu. We found that rhesus BST-2 carrying the transmembrane (TM) domain of human BST-2 is susceptible to HIV-1 Vpu. Finally, a single-amino-acid change in the rhesus BST-2 TM domain was sufficient to confer Vpu sensitivity.

Highlights

Efficient virus release from HIV-infected cells is regulated by its Vpu gene product (Strebel et al, 1988; Terwilliger et al, 1989)
It was reported that HIV-1 Vpu can target human BST-2 but is unable to interfere with the function of murine or simian BST-2
We found that rhesus BST-2 carrying the transmembrane (TM) domain of human BST-2 is susceptible to HIV-1 Vpu

Summary

Introduction

Efficient virus release from HIV-infected cells is regulated by its Vpu gene product (Strebel et al, 1988; Terwilliger et al, 1989). IFN-treatment of Vpu-independent cell-types created a Vpu-dependent phenotype and inhibited the release of HIV-1 and related retroviruses and affected secretion of unrelated viruses such as porcine endogenous retrovirus (PERV), Ebola, Lassa, Marburg, endogenous betaretrovirus of sheep (enJSRV), and KSHV (Neil et al, 2007; Jouvenet et al, 2009; Kaletsky et al, 2009; Sakuma et al, 2009b; Arnaud et al, 2010; Mattiuzzo et al, 2010) These observations suggested that the Vpu-sensitive restriction factor was not specific to HIV but belonged to a family of interferoninducible genes with general antiviral properties. Taken together these data provided strong evidence that BST-2 was the host factor whose inhibitory effect on virus release was counteracted by Vpu

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