Leske, A.; Waßmann, I.; Schnepel, K.; Shifflett, K.; Holzerland, J.; Bostedt, L.; Bohn, P.; Mettenleiter, T.C.; Briggiler, A.M.; Brignone, J.; Enria, D.; Cordo, S.M.; Hoenen, T.; Groseth, A. "Assessing cross-reactivity of Junín virus-directed neutralizing antibodies" (2019) Antiviral Research. 163:106-116
Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor


Arenaviruses cause several viral hemorrhagic fevers endemic to Africa and South America. The respective causative agents are classified as biosafety level (BSL) 4 pathogens. Unlike for most other BSL4 agents, for the New World arenavirus Junín virus (JUNV) both a highly effective vaccination (Candid#1) and a post-exposure treatment, based on convalescent plasma transfer, are available. In particular, neutralizing antibodies (nAbs) represent a key protective determinant in JUNV infection, which is supported by the correlation between successful passive antibody therapy and the levels of nAbs administered. Unfortunately, comparable resources for the management of other closely related arenavirus infections are not available. Given the significant challenges inherent in studying BSL4 pathogens, our goal was to first assess the suitability of a JUNV transcription and replication-competent virus-like particle (trVLP) system for measuring virus neutralization under BSL1/2 conditions. Indeed, we could show that infection with JUNV trVLPs is glycoprotein (GP) dependent, that trVLP input has a direct correlation to reporter readout, and that these trVLPs can be neutralized by human serum with kinetics similar to those obtained using authentic virus. These properties make trVLPs suitable for use as a proxy for virus in neutralization assays. Using this platform we then evaluated the potential of JUNV nAbs to cross-neutralize entry mediated by GPs from other arenaviruses using JUNV (strain Romero)-based trVLPs bearing GPs either from other JUNV strains, other closely related New World arenaviruses (e.g. Tacaribe, Machupo, Sabiá), or the distantly related Lassa virus. While nAbs against the JUNV vaccine strain are also active against a range of other JUNV strains, they appear to have little or no capacity to neutralize other arenavirus species, suggesting that therapy with whole plasma directed against another species is unlikely to be successful and that the targeted development of cross-specific monoclonal antibody-based resources is likely needed. Such efforts will be supported by the availability of this BSL1/2 screening platform which provides a rapid and easy means to characterize the potency and reactivity of anti-arenavirus neutralizing antibodies against a range of arenavirus species. © 2019 Elsevier B.V.


Documento: Artículo
Título:Assessing cross-reactivity of Junín virus-directed neutralizing antibodies
Autor:Leske, A.; Waßmann, I.; Schnepel, K.; Shifflett, K.; Holzerland, J.; Bostedt, L.; Bohn, P.; Mettenleiter, T.C.; Briggiler, A.M.; Brignone, J.; Enria, D.; Cordo, S.M.; Hoenen, T.; Groseth, A.
Filiación:Junior Research Group Arenavirus Biology, Friedrich-Loeffler-Institut, Greifswald, Insel Riems, Germany
Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Hamilton, MT, United States
Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Greifswald, Insel Riems, Germany
Instituto Nacional de Enfermedades Virales Humanas, ANLIS, Pergamino, Argentina
Laboratory of Virology, IQUIBICEN-Department of Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
Palabras clave:Antibody cross-reactivity; Arenavirus; JunÍn virus; Neutralization assay; Neutralizing antibodies; Transcription and replication competent virus-like particle (trVLP) assay; glycoprotein; monoclonal antibody; neutralizing antibody; antibody specificity; Arenaviridae; Article; correlation analysis; cross reaction; Junin virus; New World arenavirus; nonhuman; priority journal; virus neutralization; virus particle; virus replication; virus strain; virus transcription
Página de inicio:106
Página de fin:116
Título revista:Antiviral Research
Título revista abreviado:Antiviral Res.


  • Aleksandrowicz, P., Marzi, A., Biedenkopf, N., Beimforde, N., Becker, S., Hoenen, T., Feldmann, H., Schnittler, H.J., Ebola virus enters host cells by macropinocytosis and clathrin-mediated endocytosis (2011) J. Infect. Dis., 204, pp. S957-S967
  • Brouillette, R.B., Phillips, E.K., Ayithan, N., Maury, W., Differences in glycoprotein complex receptor binding site accessibility prompt poor cross-reactivity of neutralizing antibodies between closely related arenaviruses (2017) J. Virol., 91
  • Buchholz, U.J., Finke, S., Conzelmann, K.K., Generation of bovine respiratory syncytial virus (BRSV) from cDNA: BRSV NS2 is not essential for virus replication in tissue culture, and the human RSV leader region acts as a functional BRSV genome promoter (1999) J. Virol., 73, pp. 251-259
  • Charrel, R.N., de Lamballerie, X., Arenaviruses other than Lassa virus (2003) Antivir. Res., 57, pp. 89-100
  • Clark, L.E., Mahmutovic, S., Raymond, D.D., Dilanyan, T., Koma, T., Manning, J.T., Shankar, S., Abraham, J., Vaccine-elicited receptor-binding site antibodies neutralize two New World hemorrhagic fever arenaviruses (2018) Nat. Commun., 9, p. 1884
  • Dunham, E.C., Leske, A., Shifflett, K., Watt, A., Feldmann, H., Hoenen, T., Groseth, A., Lifecycle modelling systems support inosine monophosphate dehydrogenase (IMPDH) as a pro-viral factor and antiviral target for New World arenaviruses (2018) Antivir. Res., 157, pp. 140-150
  • Enria, D., Franco, S.G., Ambrosio, A., Vallejos, D., Levis, S., Maiztegui, J., Current status of the treatment of Argentine hemorrhagic fever (1986) Med. Microbiol. Immunol., 175, pp. 173-176
  • Enria, D.A., Briggiler, A.M., Fernandez, N.J., Levis, S.C., Maiztegui, J.I., Importance of dose of neutralising antibodies in treatment of Argentine haemorrhagic fever with immune plasma (1984) Lancet, 2, pp. 255-256
  • Enria, D.A., Briggiler, A.M., Sanchez, Z., Treatment of Argentine hemorrhagic fever (2008) Antivir. Res., 78, pp. 132-139
  • Golden, J.W., Beitzel, B., Ladner, J.T., Mucker, E.M., Kwilas, S.A., Palacios, G., Hooper, J.W., An attenuated Machupo virus with a disrupted L-segment intergenic region protects Guinea pigs against lethal Guanarito virus infection (2017) Sci. Rep., 7, p. 4679
  • Groseth, A., Wolff, S., Strecker, T., Hoenen, T., Becker, S., Efficient budding of the tacaribe virus matrix protein z requires the nucleoprotein (2010) J. Virol., 84, pp. 3603-3611
  • Koishi, A.C., Suzukawa, A.A., Zanluca, C., Camacho, D.E., Comach, G., Duarte Dos Santos, C.N., Development and evaluation of a novel high-throughput image-based fluorescent neutralization test for detection of Zika virus infection (2018) PLoS Neglected Trop. Dis., 12
  • Koma, T., Patterson, M., Huang, C., Seregin, A.V., Maharaj, P.D., Miller, M., Smith, J.N., Paessler, S., Machupo virus expressing GPC of the Candid#1 vaccine strain of junin virus is highly attenuated and immunogenic (2016) J. Virol., 90, pp. 1290-1297
  • Li, W., Cao, S., Zhang, Q., Li, J., Zhang, S., Wu, W., Qu, J., Li, D., Comparison of serological assays to titrate Hantaan and Seoul hantavirus-specific antibodies (2017) Virol. J., 14, p. 133
  • Mahmutovic, S., Clark, L., Levis, S.C., Briggiler, A.M., Enria, D.A., Harrison, S.C., Abraham, J., Molecular basis for antibody-mediated neutralization of new World hemorrhagic fever mammarenaviruses (2015) Cell Host Microbe, 18, pp. 705-713
  • Maiztegui, J.I., Fernandez, N.J., de Damilano, A.J., Efficacy of immune plasma in treatment of Argentine haemorrhagic fever and association between treatment and a late neurological syndrome (1979) Lancet, 2, pp. 1216-1217
  • Maiztegui, J.I., McKee, K.T., Jr., Barrera Oro, J.G., Harrison, L.H., Gibbs, P.H., Feuillade, M.R., Enria, D.A., Peters, C.J., Protective efficacy of a live attenuated vaccine against Argentine hemorrhagic fever. AHF Study Group (1998) J. Infect. Dis., 177, pp. 277-283
  • McCormick, J.B., Webb, P.A., Krebs, J.W., Johnson, K.M., Smith, E.S., A prospective study of the epidemiology and ecology of Lassa fever (1987) J. Infect. Dis., 155, pp. 437-444
  • Nanbo, A., Imai, M., Watanabe, S., Noda, T., Takahashi, K., Neumann, G., Halfmann, P., Kawaoka, Y., Ebolavirus is internalized into host cells via macropinocytosis in a viral glycoprotein-dependent manner (2010) PLoS Pathog., 6
  • Pan, X., Wu, Y., Wang, W., Zhang, L., Xiao, G., Novel neutralizing monoclonal antibodies against Junin virus (2018) Antivir. Res., 156, pp. 21-28
  • Putnak, J.R., de la Barrera, R., Burgess, T., Pardo, J., Dessy, F., Gheysen, D., Lobet, Y., Sun, W., Comparative evaluation of three assays for measurement of dengue virus neutralizing antibodies (2008) Am. J. Trop. Med. Hyg., 79, pp. 115-122
  • Rojek, J.M., Lee, A.M., Nguyen, N., Spiropoulou, C.F., Kunz, S., Site 1 protease is required for proteolytic processing of the glycoproteins of the South American hemorrhagic fever viruses Junin, Machupo, and Guanarito (2008) J. Virol., 82, pp. 6045-6051
  • Ruggiero, H.A., Magnoni, C., de Guerrero, L.B., Milani, H.A., Izquierdo, F.P., Milani, H.L., Weber, E.L., Persistence of antibodies and clinical evaluation in volunteers 7 to 9 Years following the vaccination against Argentine hemorrhagic fever (1981) J. Med. Virol., 7, pp. 227-232
  • Saeed, M.F., Kolokoltsov, A.A., Albrecht, T., Davey, R.A., Cellular entry of ebola virus involves uptake by a macropinocytosis-like mechanism and subsequent trafficking through early and late endosomes (2010) PLoS Pathog., 6
  • Shan, C., Ortiz, D.A., Yang, Y., Wong, S.J., Kramer, L.D., Shi, P.Y., Loeffelholz, M.J., Ren, P., Evaluation of a novel reporter virus neutralization test for serological diagnosis of zika and dengue virus infection (2017) J. Clin. Microbiol., 55, pp. 3028-3036
  • Spiegelberg, L., Wahl-Jensen, V., Kolesnikova, L., Feldmann, H., Becker, S., Hoenen, T., Genus-specific recruitment of filovirus ribonucleoprotein complexes into budding particles (2011) J. Gen. Virol., 92, pp. 2900-2905
  • Taketa-Graham, M., Powell Pereira, J.L., Baylis, E., Cossen, C., Oceguera, L., Patiris, P., Chiles, R., Forghani, B., High throughput quantitative colorimetric microneutralization assay for the confirmation and differentiation of West Nile Virus and St. Louis encephalitis virus (2010) Am. J. Trop. Med. Hyg., 82, pp. 501-504
  • Watt, A., Moukambi, F., Banadyga, L., Groseth, A., Callison, J., Herwig, A., Ebihara, H., Hoenen, T., A novel life cycle modeling system for Ebola virus shows a genome length-dependent role of VP24 in virus infectivity (2014) J. Virol., 88, pp. 10511-10524
  • Weissenbacher, M.C., Coto, C.E., Calello, M.A., Cross-protection between Tacaribe complex viruses. Presence of neutralizing antibodies against Junin virus (Argentine hemorrhagic fever) in Guinea pigs infected with Tacaribe virus (1975) Intervirology, 6, pp. 42-49
  • Weissenbacher, M.C., Coto, C.E., Calello, M.A., Rondinone, S.N., Damonte, E.B., Frigerio, M.J., Cross-protection in nonhuman primates against Argentine hemorrhagic fever (1982) Infect. Immun., 35, pp. 425-430
  • World Health Organization, Lassa Fever R&D Roadmap (2018),; Zeitlin, L., Geisbert, J.B., Deer, D.J., Fenton, K.A., Bohorov, O., Bohorova, N., Goodman, C., Geisbert, T.W., Monoclonal antibody therapy for Junin virus infection (2016) Proc. Natl. Acad. Sci. U. S. A., 113, pp. 4458-4463
  • Zeltina, A., Krumm, S.A., Sahin, M., Struwe, W.B., Harlos, K., Nunberg, J.H., Crispin, M., Bowden, T.A., Convergent immunological solutions to Argentine hemorrhagic fever virus neutralization (2017) Proc. Natl. Acad. Sci. U. S. A., 114, pp. 7031-7036


---------- APA ----------
Leske, A., Waßmann, I., Schnepel, K., Shifflett, K., Holzerland, J., Bostedt, L., Bohn, P.,..., Groseth, A. (2019) . Assessing cross-reactivity of Junín virus-directed neutralizing antibodies. Antiviral Research, 163, 106-116.
---------- CHICAGO ----------
Leske, A., Waßmann, I., Schnepel, K., Shifflett, K., Holzerland, J., Bostedt, L., et al. "Assessing cross-reactivity of Junín virus-directed neutralizing antibodies" . Antiviral Research 163 (2019) : 106-116.
---------- MLA ----------
Leske, A., Waßmann, I., Schnepel, K., Shifflett, K., Holzerland, J., Bostedt, L., et al. "Assessing cross-reactivity of Junín virus-directed neutralizing antibodies" . Antiviral Research, vol. 163, 2019, pp. 106-116.
---------- VANCOUVER ----------
Leske, A., Waßmann, I., Schnepel, K., Shifflett, K., Holzerland, J., Bostedt, L., et al. Assessing cross-reactivity of Junín virus-directed neutralizing antibodies. Antiviral Res. 2019;163:106-116.