2-thio-6-azauridine inhibits Vpu mediated BST-2 degradation.

Quan Zhang,Yongxin Zhang,Ling Ma,Yuming Huang,Shan Cen,Jing Wang,Fei Guo,Jinming Zhou,Yang Chen,Zeyun Mi,Xiaoyu Li,Jiwei Ding

doi:10.1186/s12977-016-0247-z

Abstract

Backgroud BST-2 is an interferon-induced host restriction factor that inhibits the release of diverse mammalian enveloped viruses from infected cells by physically trapping the newly formed virions onto the host cell surface. Human Immunodeficiency Virus-1 (HIV-1) encodes an accessory protein Vpu that antagonizes BST-2 by down-regulating BST-2 from the cell surface.ResultsUsing a cell-based ELISA screening system, we have discovered a lead compound, 2-thio-6-azauridine, that restores cell surface BST-2 level in the presence of Vpu. This compound has no effect on the expression of BST-2 and Vpu, but inhibits Vpu-mediated BST-2 down-regulation and exerts no effect on Vpu-induced down-regulation of CD4 or KSHV K5 protein induced BST-2 down-regulation. 2-thio-6-azauridine suppresses HIV-1 production in a BST-2-dependent manner. Further results indicate that 2-thio-6-azauridine does not interrupt the interaction of BST-2 with Vpu and β-TrCP2, but decreases BST-2 ubiquitination.ConclusionOur study demonstrates the feasibility of using small molecules to target Vpu function and sensitize wild type HIV-1 to BST-2-mediated host restriction.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0247-z) contains supplementary material, which is available to authorized users.

Highlights

Human bone marrow stromal cell antigen 2 (BST-2, called Tetherin, CD317 or HM1.24) was first shown to inhibit Human Immunodeficiency Virus-1 (HIV-1) production by physically trapping the newly formed virions onto the host cell surface [1, 2]
2‐thio‐6‐azauridine inhibits Vpu‐mediated down‐regulation of cell surface BST‐2 We have previously developed a high-throughput cellbased ELISA assay for screening small molecules that prevent HIV-1 Vpu from degrading BST-2 [39]
Our results indicate that 2-thio-6-azauridine does not affect the expression of BST-2 or Vpu, which suggests that 2-thio-6-azauridine restores the level of cell surface BST-2 by inhibiting Vpu-mediated BST-2 degradation

Summary

Introduction

Human bone marrow stromal cell antigen 2 (BST-2, called Tetherin, CD317 or HM1.24) was first shown to inhibit HIV-1 production by physically trapping the newly formed virions onto the host cell surface [1, 2]. BST-2 is a 28- to 36-kDa type II integral membrane glycoprotein, located to lipid rafts at the plasma membrane and the trans Golgi network (TGN). It consists of four domains, a short N-terminal cytoplasmic tail, an N-terminal transmembrane region (TMR), an extracellular coiled-coil domain and a C-terminal glycosyl-phosphatidylinositol (GPI). Vpu is an integral membrane protein, which belongs to type I integral membrane protein family It performs two distinct functions in HIV-1 infection: causing CD4 degradation in the endoplasmic reticulum and promoting viral particle release by counteracting BST-2 [21,22,23,24,25,26,27,28]. Since studies have demonstrated decreases in levels of both the total cellular BST-2 as well as the cell

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Conclusion