prM-reactive antibodies reveal a role for partially mature virions in dengue virus pathogenesis

Cleavage of the flavivirus premembrane (prM) structural protein during maturation can be inefficient. The contribution of partially mature flavivirus virions that retain uncleaved prM to pathogenesis during primary infection is unknown. To investigate this question, we characterized the functional p...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 120; no. 3; p. e2218899120
Main Authors A. Dowd, Kimberly, Sirohi, Devika, D. Speer, Scott, VanBlargan, Laura A., Chen, Rita E., Mukherjee, Swati, Whitener, Bradley M., Govero, Jennifer, Aleshnick, Maya, Larman, Bridget, Sukupolvi-Petty, Soila, Sevvana, Madhumati, Miller, Andrew S., Klose, Thomas, Zheng, Aihua, Koenig, Scott, Kielian, Margaret, Kuhn, Richard J., Diamond, Michael S., Pierson, Theodore C.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 17.01.2023
Subjects
Alanine
Animals
Antibodies, Monoclonal
Antibodies, Viral
Antigens
Biological Sciences
Cryoelectron Microscopy
Dengue
Dengue fever
Dengue Virus
Genetic modification
Lethality
Maturation
Mice
Monoclonal antibodies
Pathogenesis
Scanning mutagenesis
Vector-borne diseases
Viral Envelope Proteins - metabolism
Virion - metabolism
Virions
Viruses
antibody-dependent enhancement
prM antibody
virion maturation
dengue virus
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Summary:Cleavage of the flavivirus premembrane (prM) structural protein during maturation can be inefficient. The contribution of partially mature flavivirus virions that retain uncleaved prM to pathogenesis during primary infection is unknown. To investigate this question, we characterized the functional properties of newly-generated dengue virus (DENV) prM-reactive monoclonal antibodies (mAbs) in vitro and using a mouse model of DENV disease. Anti-prM mAbs neutralized DENV infection in a virion maturation state–dependent manner. Alanine scanning mutagenesis and cryoelectron microscopy of anti-prM mAbs in complex with immature DENV defined two modes of attachment to a single antigenic site. In vivo, passive transfer of intact anti-prM mAbs resulted in an antibody-dependent enhancement of disease. However, protection against DENV-induced lethality was observed when the transferred mAbs were genetically modified to inhibit their ability to interact with Fcγ receptors. These data establish that in addition to mature forms of the virus, partially mature infectious prM + virions can also contribute to pathogenesis during primary DENV infections.
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Edited by Diane Griffin, Johns Hopkins University, Baltimore, MD; received November 9, 2022; accepted November 28, 2022
5Present address: Leinco Technologies, Fenton, MO 63026.
7Retired.
8Present address: Large Molecules Research, Sanofi, Framingham, MA 01701.
2Present address: Virology and Vaccine Discovery, Microbial Sciences, AstraZeneca, Gaithersburg, MD 20878.
3Present address: Viral Pathogenesis Section, Laboratory of Viral Diseases, National Institutes of Health, Bethesda, MD 20892.
4Present address: KSQ Therapeutics, Cambridge, MA 02139.
9Present address: State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
1K.A.D. and D.S. contributed equally to this work.
6Present address: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2218899120