Cryo-EM structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity

Long, Feng; Fong, Rachel H.; Austin, Stephen K.; Chen, Zhenguo; Klose, Thomas; Fokine, Andrei; Liu, Yue; Porta, Jason; Sapparapu, Gopal; Akahata, Wataru; Doranz, Benjamin J.; Crowe, James E.; Diamond, Michael S.; Rossmann, Michael G.

doi:10.1073/pnas.1515558112

Cryo-EM structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity

Journal Article · Mon Oct 26 00:00:00 EDT 2015 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1515558112· OSTI ID:1229894

Long, Feng ^[1]; Fong, Rachel H. ^[2]; Austin, Stephen K. ^[3]; Chen, Zhenguo ^[1]; Klose, Thomas ^[1]; Fokine, Andrei ^[1]; Liu, Yue ^[1]; Porta, Jason ^[1]; Sapparapu, Gopal ^[4]; Akahata, Wataru ^[5]; Doranz, Benjamin J. ^[2]; Crowe, James E. ^[6]; Diamond, Michael S. ^[3]; Rossmann, Michael G. ^[1]

Purdue Univ., West Lafayette, IN (United States). Dept. of Biological Sciences
Integral Molecular, Inc., Philadelphia, PA (United States)
Washington Univ., St. Louis, MO (United States). School of Medicine. Dept. of Medicine, Molecular Microbiology, Pathology, and Immunology
Vanderbilt Univ., Nashville, TN (United States). Dept. of Pediatrics
VLP Therapeutics, LLC, Gaithersburg, MD (United States)
Vanderbilt Univ., Nashville, TN (United States). Dept. of Pediatrics. Dept. of Pathology, Microbiology, and Immunology. Vanderbilt Univ. Medical Center. Vanderbilt Vaccine Center

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes severe acute and chronic disease in humans. Although highly inhibitory murine and human monoclonal antibodies (mAbs) have been generated, the structural basis of their neutralizing activity remains poorly characterized. In this paper, we determined the cryo-EM structures of chikungunya virus-like particles complexed with antibody fragments (Fab) of two highly protective human mAbs, 4J21 and 5M16, that block virus fusion with host membranes. Both mAbs bind primarily to sites within the A and B domains, as well as to the B domain’s β-ribbon connector of the viral glycoprotein E2. The footprints of these antibodies on the viral surface were consistent with results from loss-of-binding studies using an alanine scanning mutagenesis-based epitope mapping approach. The Fab fragments stabilized the position of the B domain relative to the virus, particularly for the complex with 5M16. Finally, this finding is consistent with a mechanism of neutralization in which anti-CHIKV mAbs that bridge the A and B domains impede movement of the B domain away from the underlying fusion loop on the E1 glycoprotein and therefore block the requisite pH-dependent fusion of viral and host membranes.

View Accepted Manuscript (DOE)

Research Organization:: Purdue Univ., West Lafayette, IN (United States); Vanderbilt Univ., Nashville, TN (United States)

Sponsoring Organization:: National Inst. of Health (NIH) (United States); USDOE Office of Science (SC)

Contributing Organization:: Integral Molecular, Inc., Philadelphia, PA (United States); VLP Therapeutics, LLC, Gaithersburg, MD (United States); Washington Univ., St. Louis, MO (United States)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1229894

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 45 Vol. 112; ISSN 0027-8424

Publisher:: National Academy of Sciences, Washington, DC (United States)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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