Proteasome Inhibitor PS-341 Effectively Blocks Infection by the Severe Fever with Thrombocytopenia Syndrome Virus  

作　　者：Sihua Liu Hongyun Liu Keke Zhang Xueping Li Yuqin Duan Zhiyun Wang Tao Wang 

机构地区：[1]School of Life Sciences,Tianjin University,Tianjin 300073,China [2]School of Environmental Science and Engineering,Tianjin University,Tianjin 300073,China

出　　处：《Virologica Sinica》2019年第5期572-582,共11页中国病毒学（英文版）

基　　金：supported by the National Science Foundation of China (31270201);the National Key Research and Development Program of China (2017YFA0205102);the Seed Foundation of Tianjin University (2014XRX-0026);the National Science Foundation of Tianjin (No.16JCQNJC09800)

摘　　要：Severe fever with thrombocytopenia syndrome(SFTS)is an emerging hemorrhagic fever disease caused by SFTSV,a newly discovered phlebovirus that is named after the disease.Currently,no effective vaccines or drugs are available for use against SFTSV infection,as our understanding of the viral pathogenesis is limited.Bortezomib(PS-341),a dipeptideboronic acid analog,is the first clinically approved proteasome inhibitor for use in humans.In this study,the antiviral efficacy of PS-341 against SFTSV infection was tested in human embryonic kidney HEK293T(293T)cells.We employed four different assays to analyze the antiviral ability of PS-341 and determined that PS-341 inhibited the proliferation of SFTSV in 293T cells under various treatment conditions.Although PS-341 did not affect the virus absorption,PS-341 treatment within a non-toxic concentration range resulted in a significant reduction of progeny viral titers in infected cells.Dual-luciferase reporter assays and Western blot analysis revealed that PS-341 could reverse the SFTSV-encoded nonstructural protein(NS)mediated degradation of retinoic acid-inducible gene-1(RIG-I),thereby antagonizing the inhibitory effect of NSs on interferons and blocking virus replication.In addition,we observed that inhibition of apoptosis promotes virus replication.These results indicate that targeting of cellular interferon pathways and apoptosis during acute infection might serve as the bases of future therapeutics for the treatment of SFTSV infections.Severe fever with thrombocytopenia syndrome(SFTS) is an emerging hemorrhagic fever disease caused by SFTSV, a newly discovered phlebovirus that is named after the disease. Currently, no effective vaccines or drugs are available for use against SFTSV infection, as our understanding of the viral pathogenesis is limited. Bortezomib(PS-341), a dipeptideboronic acid analog, is the first clinically approved proteasome inhibitor for use in humans. In this study, the antiviral efficacy of PS-341 against SFTSV infection was tested in human embryonic kidney HEK293 T(293 T) cells. We employed four different assays to analyze the antiviral ability of PS-341 and determined that PS-341 inhibited the proliferation of SFTSV in 293 T cells under various treatment conditions. Although PS-341 did not affect the virus absorption, PS-341 treatment within a non-toxic concentration range resulted in a significant reduction of progeny viral titers in infected cells.Dual-luciferase reporter assays and Western blot analysis revealed that PS-341 could reverse the SFTSV-encoded nonstructural protein(NS) mediated degradation of retinoic acid-inducible gene-1(RIG-I), thereby antagonizing the inhibitory effect of NSs on interferons and blocking virus replication. In addition, we observed that inhibition of apoptosis promotes virus replication. These results indicate that targeting of cellular interferon pathways and apoptosis during acute infection might serve as the bases of future therapeutics for the treatment of SFTSV infections.

关 键 词：BORTEZOMIB PS-341 Severe fever with thrombocytopenia syndrome virus(SFTSV) IFN-Β Apoptosis 

分 类 号：R73[医药卫生—肿瘤]