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.
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 -