Subjects: Biology >> Biophysics submitted time 2016-05-11
Mi, Zeyun
Ding, Jiwei
Zhang, Quan
Ma, Ling
Shan, Guangzhi
Li, Xiaoyu
Zhou, Jinming
Cen, Shan
Mi, Zeyun
Ding, Jiwei
Zhang, Quan
Ma, Ling
Shan, Guangzhi
Li, Xiaoyu
Zhou, Jinming
Cen, Shan
Zhao, Jianyuan
Wei, Tao
Liu, Zhenlong
Liang, Chen
Abstract： Human BST-2 inhibits HIV-1 replication by tethering nascent virions to the cell surface. HIV-1 codes Vpu that counteracts BST-2 by down-regulating this restriction factor from the cell surface. This important function makes Vpu a potential therapeutic target. Yet, no agents have been reported to block Vpu from antagonizing BST-2. In this study, we report a small molecule compound IMB-LA that abrogates the function of Vpu and thereby strongly suppresses HIV-1 replication by sensitizing the virus to BST-2 restriction. Further studies revealed that IMB-LA specifically inhibits Vpu-mediated degradation of BST-2 and restores the expression of BST-2 at the cell surface. Although IMB-LA does not prevent Vpu from interacting with BST-2 or beta-TrCP2-containing ubiquitin E3 ligase, sorting of BST-2 into lysosomes in Vpu-expressing cells is blocked by IMB-LA. Most importantly, HIV-1 release and infection is inhibited by IMB-LA only in BST-2-expressing cells. In summary, results herein demonstrated that IMB-LA could specifically inhibit the degradation of BST-2 induced by Vpu, and impair HIV-1 replication in a BST-2 dependent manner, suggesting the feasibility of utilizing small molecule compounds to disable the antagonist function of Vpu and thereby expose HIV-1 to the restriction by BST-2.
Peer Review Status:
Awaiting Review
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