TY - JOUR
T1 - prM-reactive antibodies reveal a role for partially mature virions in dengue virus pathogenesis
AU - Dowd, Kimberly A.
AU - Sirohi, Devika
AU - Speer, Scott D.
AU - VanBlargan, Laura A.
AU - Chen, Rita E.
AU - Mukherjee, Swati
AU - Whitener, Bradley M.
AU - Govero, Jennifer
AU - Aleshnick, Maya
AU - Larman, Bridget
AU - Sukupolvi-Petty, Soila
AU - Sevvana, Madhumati
AU - Miller, Andrew S.
AU - Klose, Thomas
AU - Zheng, Aihua
AU - Koenig, Scott
AU - Kielian, Margaret
AU - Kuhn, Richard J.
AU - Diamond, Michael S.
AU - Pierson, Theodore C.
N1 - Publisher Copyright:
Copyright © 2023 the Author(s). Published by PNAS.
PY - 2023/1/17
Y1 - 2023/1/17
N2 - 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.
AB - 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.
KW - antibody-dependent enhancement
KW - dengue virus
KW - prM antibody
KW - virion maturation
UR - http://www.scopus.com/inward/record.url?scp=85146363723&partnerID=8YFLogxK
U2 - 10.1073/pnas.2218899120
DO - 10.1073/pnas.2218899120
M3 - Article
C2 - 36638211
AN - SCOPUS:85146363723
SN - 0027-8424
VL - 120
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
IS - 3
M1 - e2218899120
ER -