The Neutralizing Monoclonal Antibodies against SFTS Group Bandaviruses Suggest New Targets of Specific or Broad-Spectrum Antivirals

Liyan Fu Brain Science and Advanced Technology Institute, Wuhan University of Science and Technology, Wuhan, China;
Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China;

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Lang Xu Brain Science and Advanced Technology Institute, Wuhan University of Science and Technology, Wuhan, China;

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Jin Qian Brain Science and Advanced Technology Institute, Wuhan University of Science and Technology, Wuhan, China;
Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China;

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Xiaoli Wu Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China;

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Zhiying Wang Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China;

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Hualin Wang Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China;

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Dan Liu Brain Science and Advanced Technology Institute, Wuhan University of Science and Technology, Wuhan, China;

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Fei Deng Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China;

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Shu Shen Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China;
Hubei Jiangxia Laboratory, Wuhan, China

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ABSTRACT.

Severe fever with thrombocytopenia syndrome virus (SFTSV), Heartland virus (HRTV) and Guertu virus (GTV) belong to the severe fever with thrombocytopenia syndrome/Heartland group of genus Bandavirus in the family Phenuiviridae of order Bunyavirales. Severe fever with thrombocytopenia syndrome virus and HRTV, identified from ticks from Asia and America, respectively, are important pathogens causing severe febrile diseases in humans. Guertu virus, closely related to these two viruses, is a potential pathogen, but no confirmed infection has been identified. So far, human-derived neutralizing monoclonal antibodies (mAbs) against SFTSV have been identified as having a great potential to be developed as antivirals; however, there is still a lack of neutralizing mAbs to GTV and HRTV. In this study, five neutralizing the mAbs against GTV and HRTV were obtained by hybridoma screening technology, four of which (14B4, 14D8, and 20D4 derived from GTV, and 27C8 derived from HRTV) showed cross reactivity and neutralization to all three viruses, and one derived from HRTV (10D6) neutralized HRTV specifically. The possible mechanisms of mAbs cross neutralization among the three viruses are discussed by analyzing their glycoprotein (GP) sequences and structures. Generating these neutralizing mAbs provides important antiviral candidates against GTV, HRTV, and SFTSV despite their differential activities, and their protective effect could be further evaluated in virus-infected mice. Their differential neutralizing efficiency and specificity further suggested that the three viruses share common mechanisms on the basis of GP functioning, and that HRTV poses a unique mechanism that differs from the other viruses. These findings shed light on developing broad-spectrum antiviral strategies against bandaviruses and promoting an understanding of the bandavirus infection process.

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Author Notes

Financial support: This work was supported by the National Key Research and Development Project (Grant no. 2018YFE0200400), National Natural Science Foundation of China (Grant no. U20A20135); and the EVAg-Global Project (Grant no. 871029), Natural Science Foundation of China (Grant no. 72174159).

Disclosures: L. Fu, S. Shen, F. Deng, J. Qian, X. Wu, Z. Wang, and D. Liu are the inventors of two pending patent applications filed on the reported antibodies. Animal experiments were approved by the ethics committee of Wuhan Institute of Virology, Chinese Academy of Sciences (Approval no. WIVA33202004).

Authors’ addresses: Liyan Fu and Jin Qian, Brain Science and Advanced Technology Institute, Wuhan University of Science and Technology, Wuhan, China, and Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China, E-mails: fuliyan1218@163.com and qianjin09222@163.com. Lang Xu and Dan Liu, Brain Science and Advanced Technology Institute, Wuhan University of Science and Technology, Wuhan, China, E-mails: xulang@wust.edu.cn and liudan125@wust.edu.cn. Xiaoli Wu, Zhiying Wang, Hualin Wang, and Fei Deng, Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China, E-mails: xlwuwh@163.com, wzhy@wh.iov.cn, h.wang@wh.iov.cn, and df@wh.iov.cn. Shu Shen, Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China, and Hubei Jiangxia Laboratory, Wuhan, China, E-mail: shenshu@wh.iov.cn.

Address correspondence to Dan Liu, Brain Science and Advanced Technology Institute, Wuhan University of Science and Technology, Wuhan 430065, China. Email: liudan125@wust.edu.cn. Fei Deng or Shu Shen, Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China. E-mails: df@wh.iov.cn or shenshu@wh.iov.cn
  • 1.

    Shen S et al., 2018. A novel tick-borne phlebovirus, closely related to severe fever with thrombocytopenia syndrome virus and Heartland virus, is a potential pathogen. Emerg Microbes Infect 7: 95.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Shi M et al., 2016. Redefining the invertebrate RNA virosphere. Nature 540: 539543.

  • 3.

    Abudurexiti A et al., 2019. Taxonomy of the order Bunyavirales: update 2019. Arch Virol 164: 19491965.

  • 4.

    Yu XJ et al., 2011. Fever with thrombocytopenia associated with a novel bunyavirus in China. N Engl J Med 364: 15231532.

  • 5.

    Li J , Li S , Yang L , Cao P , Lu J , 2021. Severe fever with thrombocytopenia syndrome virus: a highly lethal bunyavirus. Crit Rev Microbiol 47: 112125.

  • 6.

    Zhan J , Wang Q , Cheng J , Hu B , Li J , Zhan F , Song Y , Guo D , 2017. Current status of severe fever with thrombocytopenia syndrome in China. Virol Sin 32: 5162.

  • 7.

    Zohaib A et al., 2020. Serologic evidence of severe fever with thrombocytopenia syndrome virus and related viruses in Pakistan. Emerg Infect Dis 26: 15131516.

  • 8.

    Tran XC , Yun Y , Van An L , Kim SH , Thao NTP , Man PKC , Yoo JR , Heo ST , Cho NH , Lee KH , 2019. Endemic severe fever with thrombocytopenia syndrome, Vietnam. Emerg Infect Dis 25: 10291031.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Brault AC , Savage HM , Duggal NK , Eisen RJ , Staples JE , 2018. Heartland virus epidemiology, vector association, and disease potential. Viruses 10: 498.

  • 10.

    CDC , 2022. Heartland Virus Disease (Heartland): Statistics & Maps. Available at: https://www.cdc.gov/heartland-virus/statistics/index.html. Accessed November 22, 2022.

    • PubMed
    • Export Citation
  • 11.

    Gauci PJ , McAllister J , Mitchell IR , St George TD , Cybinski DH , Davis SS , Gubala AJ , 2015. Hunter Island group phlebovirus in ticks, Australia. Emerg Infect Dis 21: 22462248.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Wang J et al., 2014. Novel phlebovirus with zoonotic potential isolated from ticks, Australia. Emerg Infect Dis 20: 10401043.

  • 13.

    Yoo JR , Heo ST , Kim M , Song SW , Boo JW , Lee KH , 2019. Seroprevalence of severe fever with thrombocytopenia syndrome in the agricultural population of Jeju Island, Korea, 2015–2017. Infect Chemother 51: 337344.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Shepard HM , Phillips GL , Thanos CD , Feldmann M , 2017. Developments in therapy with monoclonal antibodies and related proteins. Clin Med (Lond) 17: 220232.

  • 15.

    Diamant E , Torgeman A , Ozeri E , Zichel R , 2015. Monoclonal antibody combinations that present synergistic neutralizing activity: a platform for next-generation anti-toxin drugs. Toxins (Basel) 7: 18541881.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Zhang Y et al., 2017. Isolation, characterization, and phylogenic analysis of three new severe fever with thrombocytopenia syndrome bunyavirus strains derived from Hubei Province, China. Virol Sin 32: 8996.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Shen S , Gan YY , Wang ML , Hu ZH , Wang HL , Deng F , 2012. Incorporation of GP64 into Helicoverpa armigera nucleopolyhedrovirus enhances virus infectivity in vivo and in vitro. J Gen Virol 93: 27052711.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Dai S , Zhang T , Zhang Y , Wang H , Deng F , 2018. Zika virus baculovirus-expressed virus-like particles induce neutralizing antibodies in mice. Virol Sin 33: 213226.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Zhang M , Du Y , Yang L , Zhan L , Yang B , Huang X , Xu B , Morita K , Yu F , 2022. Development of monoclonal antibody based IgG and IgM ELISA for diagnosis of severe fever with thrombocytopenia syndrome virus infection. Braz J Infect Dis 26: 102386.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Wu Y et al., 2017. Structures of phlebovirus glycoprotein Gn and identification of a neutralizing antibody epitope. Proc Natl Acad Sci USA 114: E7564E7573.

  • 21.

    Halldorsson S , Behrens AJ , Harlos K , Huiskonen JT , Elliott RM , Crispin M , Brennan B , Bowden TA , 2016. Structure of a phleboviral envelope glycoprotein reveals a consolidated model of membrane fusion. Proc Natl Acad Sci USA 113: 71547159.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Zhu Y , Wu Y , Chai Y , Qi J , Peng R , Feng WH , Gao GF , 2017. The postfusion structure of the Heartland virus Gc glycoprotein supports taxonomic separation of the bunyaviral families Phenuiviridae and Hantaviridae. J Virol 92: e01558-17.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Guo X et al., 2013. Human antibody neutralizes severe fever with thrombocytopenia syndrome virus, an emerging hemorrhagic fever virus. Clin Vaccine Immunol 20: 14261432.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Wu Y et al., 2017. Structures of phlebovirus glycoprotein Gn and identification of a neutralizing antibody epitope. Proc Natl Acad Sci USA 114: E7564E7573.

  • 25.

    Kim KH , Kim J , Ko M , Chun JY , Kim H , Kim S , Min JY , Park WB , Oh MD , Chung J , 2019. An anti-Gn glycoprotein antibody from a convalescent patient potently inhibits the infection of severe fever with thrombocytopenia syndrome virus. PLoS Pathog 15: e1007375.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Deng F , Shen S , Wu X , Moming A , Hu S , Wang H , Zhang T , 2022. A neutralizing monoclonal antibody against SFTSV and its application [P]. CN patent: CN113980125A. 2022.01.28.

    • PubMed
    • Export Citation
  • 27.

    McMullan LK et al., 2012. A new phlebovirus associated with severe febrile illness in Missouri. N Engl J Med 367: 834841.

  • 28.

    Wang B , Huang B , Li X , Guo Y , Qi G , Ding Y , Gao H , Zhang J , Wu X , Fang L , 2022. Development of functional anti-Gn nanobodies specific for SFTSV based on next generation sequencing and proteomics. Protein Sci 31: e4461.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Dai ZN et al., 2022. Effect of genomic variations in severe fever with thrombocytopenia syndrome virus on the disease lethality. Emerg Microbes Infect 11: 16721682.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Wu X et al., 2021. Novel SFTSV phylogeny reveals new reassortment events and migration routes. Virol Sin 36: 300310.

  • 31.

    Lv Q , Zhang H , Tian L , Zhang R , Zhang Z , Li J , Tong Y , Fan H , Carr MJ , Shi W , 2017. Novel sub-lineages, recombinants and reassortants of severe fever with thrombocytopenia syndrome virus. Ticks Tick Borne Dis 8: 385390.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Yoshikawa T et al., 2015. Phylogenetic and geographic relationships of severe fever with thrombocytopenia syndrome virus in China, South Korea, and Japan. J Infect Dis 212: 889898.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Zhang Y et al., 2017. Isolation, characterization, and phylogenic analysis of three new severe fever with thrombocytopenia syndrome bunyavirus strains derived from Hubei Province, China. Virol Sin 32: 8996.

    • PubMed
    • Search Google Scholar
    • Export Citation
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