TY - JOUR
T1 - Structural basis of a potent human monoclonal antibody against Zika virus targeting a quaternary epitope
AU - Long, Feng
AU - Doyle, Michael
AU - Fernandez, Estefania
AU - Miller, Andrew S.
AU - Klose, Thomas
AU - Sevvana, Madhumati
AU - Bryan, Aubrey
AU - Davidson, Edgar
AU - Doranz, Benjamin J.
AU - Kuhn, Richard J.
AU - Diamond, Michael S.
AU - Crowe, James E.
AU - Rossmann, Michael G.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Sheryl Kelly for help in preparing the manuscript. We thank Geeta Buda for help with cell culture as well as Yingyuan Sun and Yue Liu for their help with cryo-EM data collection and for further discussion. We thank members of the J.E.C. research laboratory (Vanderbilt University Medical Center) for their technical support, including Robin Bombardi (antibody sequence analysis, Fab synthesis, and cloning), Nurgun Kose (ELISA verification of mAb binding), Rachel Nargi (production of recombinant IgG and Fab molecules), Dina Yousif (IgG purification), and Robert Carnahan and Merissa Mayo (antibody project oversight). Cryo-EM data were collected at the Purdue University Cryo-EM Facility. The computation was supported, in part, through computational resources provided by
Funding Information:
We thank Sheryl Kelly for help in preparing the manuscript. We thank Geeta Buda for help with cell culture as well as Yingyuan Sun and Yue Liu for their help with cryo-EM data collection and for further discussion. We thank members of the J.E.C. research laboratory (Vanderbilt University Medical Center) for their technical support, including Robin Bombardi (antibody sequence analysis, Fab synthesis, and cloning), Nurgun Kose (ELISA verification of mAb binding), Rachel Nargi (production of recombinant IgG and Fab molecules), Dina Yousif (IgG purification), and Robert Carnahan and Merissa Mayo (antibody project oversight). Cryo-EM data were collected at the Purdue University Cryo-EM Facility. The computation was supported, in part, through computational resources provided by Information Technology Research Computing at Purdue University, West Lafayette, Indiana. This work was supported by US National Institutes of Health (NIH) Grants R01 AI076331 (to M.G.R. and R.J.K.), NIH R01 AI127828 (to J.E.C. and M.S.D.), NIH R01 AI073755 (to M.S.D.; subawards to M.G.R., J.E.C., and R.J.K.), NIH R01 AI104972 (to M.S.D.), HHSN272201400024C (to J.E.C.), and HHSN272201400058C (to B.J.D.).
Publisher Copyright:
© 2019 National Academy of Sciences. All Right Reserved.
PY - 2019/1/29
Y1 - 2019/1/29
N2 - Zika virus (ZIKV) is a major human pathogen and member of the Flavivirus genus in the Flaviviridae family. In contrast to most other insect-transmitted flaviviruses, ZIKV also can be transmitted sexually and from mother to fetus in humans. During recent outbreaks, ZIKV infections have been linked to microcephaly, congenital disease, and Guillain-Barré syndrome. Neutralizing antibodies have potential as therapeutic agents. We report here a 4-Å-reso-lution cryo-electron microscopy structure of the ZIKV virion in complex with Fab fragments of the potently neutralizing human monoclonal antibody ZIKV-195. The footprint of the ZIKV-195 Fab fragment expands across two adjacent envelope (E) protein protomers. ZIKV neutralization by this antibody is presumably accomplished by cross-linking the E proteins, which likely prevents formation of E protein trimers required for fusion of the viral and cellular membranes. A single dose of ZIKV-195 administered 5 days after virus inoculation showed marked protection against lethality in a stringent mouse model of infection.
AB - Zika virus (ZIKV) is a major human pathogen and member of the Flavivirus genus in the Flaviviridae family. In contrast to most other insect-transmitted flaviviruses, ZIKV also can be transmitted sexually and from mother to fetus in humans. During recent outbreaks, ZIKV infections have been linked to microcephaly, congenital disease, and Guillain-Barré syndrome. Neutralizing antibodies have potential as therapeutic agents. We report here a 4-Å-reso-lution cryo-electron microscopy structure of the ZIKV virion in complex with Fab fragments of the potently neutralizing human monoclonal antibody ZIKV-195. The footprint of the ZIKV-195 Fab fragment expands across two adjacent envelope (E) protein protomers. ZIKV neutralization by this antibody is presumably accomplished by cross-linking the E proteins, which likely prevents formation of E protein trimers required for fusion of the viral and cellular membranes. A single dose of ZIKV-195 administered 5 days after virus inoculation showed marked protection against lethality in a stringent mouse model of infection.
KW - Cryo-EM structure
KW - Membrane-fusion inhibition
KW - Monoclonal antibody
KW - Neutralization mechanism
KW - Zika virus
UR - http://www.scopus.com/inward/record.url?scp=85060829578&partnerID=8YFLogxK
U2 - 10.1073/pnas.1815432116
DO - 10.1073/pnas.1815432116
M3 - Article
C2 - 30642974
AN - SCOPUS:85060829578
VL - 116
SP - 1591
EP - 1596
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 5
ER -