Complex phenotypes in mosquitoes and mice associated with neutralization escape of a Dengue virus type 1 monoclonal antibody

Bimmi Shrestha; S. Kyle Austin; Kimberly A. Dowd; Abhishek N. Prasad; Soonjeon Youn; Theodore C. Pierson; Daved H. Fremont; Gregory D. Ebel; Michael S. Diamond

doi:10.1016/j.virol.2012.02.010

Complex phenotypes in mosquitoes and mice associated with neutralization escape of a Dengue virus type 1 monoclonal antibody

Bimmi Shrestha, S. Kyle Austin, Kimberly A. Dowd, Abhishek N. Prasad, Soonjeon Youn, Theodore C. Pierson, Daved H. Fremont, Gregory D. Ebel, Michael S. Diamond

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

DENV1-E106 is a monoclonal antibody (MAb) with strong neutralizing activity against all five DENV-1 genotypes and therapeutic activity in mice. Here, we evaluated the potential for DENV-1 to escape neutralization by DENV1-E106. A single mutation in domain III of the envelope protein (T329A) emerged, which conferred resistance to DENV1-E106. However, the T329A variant virus had differing phenotypes in vitro and in vivo with attenuation in cell culture yet increased infectivity in Aedes aegypti mosquitoes. Mice infected with this T329A variant still were protected against lethal infection by DENV1-E106 even though much of the neutralizing activity was lost. This study reveals the complex dynamics of neutralization escape of an inhibitory MAb against DENV, and suggests that evaluation of therapeutic MAbs requires detailed investigation in relevant hosts.

Original language	English (US)
Pages (from-to)	127-134
Number of pages	8
Journal	Virology
Volume	427
Issue number	2
DOIs	https://doi.org/10.1016/j.virol.2012.02.010
State	Published - Jun 5 2012
Externally published	Yes

Keywords

Antibody
Dengue virus
Escape
Humanization
Mice
Mosquito
Neutralization
Pathogenesis
Therapy

ASJC Scopus subject areas

Virology

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10.1016/j.virol.2012.02.010

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@article{b354b9bcb24b4edf94f92c74651a584b,

title = "Complex phenotypes in mosquitoes and mice associated with neutralization escape of a Dengue virus type 1 monoclonal antibody",

abstract = "DENV1-E106 is a monoclonal antibody (MAb) with strong neutralizing activity against all five DENV-1 genotypes and therapeutic activity in mice. Here, we evaluated the potential for DENV-1 to escape neutralization by DENV1-E106. A single mutation in domain III of the envelope protein (T329A) emerged, which conferred resistance to DENV1-E106. However, the T329A variant virus had differing phenotypes in vitro and in vivo with attenuation in cell culture yet increased infectivity in Aedes aegypti mosquitoes. Mice infected with this T329A variant still were protected against lethal infection by DENV1-E106 even though much of the neutralizing activity was lost. This study reveals the complex dynamics of neutralization escape of an inhibitory MAb against DENV, and suggests that evaluation of therapeutic MAbs requires detailed investigation in relevant hosts.",

keywords = "Antibody, Dengue virus, Escape, Humanization, Mice, Mosquito, Neutralization, Pathogenesis, Therapy",

author = "Bimmi Shrestha and Austin, {S. Kyle} and Dowd, {Kimberly A.} and Prasad, {Abhishek N.} and Soonjeon Youn and Pierson, {Theodore C.} and Fremont, {Daved H.} and Ebel, {Gregory D.} and Diamond, {Michael S.}",

note = "Funding Information: The authors thank R. Rico-Hesse, A. de Silva, and R. Tesh for providing DENV-1 strains, S. Whitehead for the infectious cDNA clone of West-Pac-74 and the BD1528 bacteria, and J. Roehrig for critical comments on the manuscript. This work was supported by the Burroughs Wellcome Fund , the intramural program of NIAID , and NIH grants R01-AI077955 , U01-AI061373 , and U54 AI057160 (Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research).",

year = "2012",

month = jun,

day = "5",

doi = "10.1016/j.virol.2012.02.010",

language = "English (US)",

volume = "427",

pages = "127--134",

journal = "Virology",

issn = "0042-6822",

publisher = "Academic Press Inc.",

number = "2",

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TY - JOUR

T1 - Complex phenotypes in mosquitoes and mice associated with neutralization escape of a Dengue virus type 1 monoclonal antibody

AU - Shrestha, Bimmi

AU - Austin, S. Kyle

AU - Dowd, Kimberly A.

AU - Prasad, Abhishek N.

AU - Youn, Soonjeon

AU - Pierson, Theodore C.

AU - Fremont, Daved H.

AU - Ebel, Gregory D.

AU - Diamond, Michael S.

N1 - Funding Information: The authors thank R. Rico-Hesse, A. de Silva, and R. Tesh for providing DENV-1 strains, S. Whitehead for the infectious cDNA clone of West-Pac-74 and the BD1528 bacteria, and J. Roehrig for critical comments on the manuscript. This work was supported by the Burroughs Wellcome Fund , the intramural program of NIAID , and NIH grants R01-AI077955 , U01-AI061373 , and U54 AI057160 (Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research).

PY - 2012/6/5

Y1 - 2012/6/5

N2 - DENV1-E106 is a monoclonal antibody (MAb) with strong neutralizing activity against all five DENV-1 genotypes and therapeutic activity in mice. Here, we evaluated the potential for DENV-1 to escape neutralization by DENV1-E106. A single mutation in domain III of the envelope protein (T329A) emerged, which conferred resistance to DENV1-E106. However, the T329A variant virus had differing phenotypes in vitro and in vivo with attenuation in cell culture yet increased infectivity in Aedes aegypti mosquitoes. Mice infected with this T329A variant still were protected against lethal infection by DENV1-E106 even though much of the neutralizing activity was lost. This study reveals the complex dynamics of neutralization escape of an inhibitory MAb against DENV, and suggests that evaluation of therapeutic MAbs requires detailed investigation in relevant hosts.

AB - DENV1-E106 is a monoclonal antibody (MAb) with strong neutralizing activity against all five DENV-1 genotypes and therapeutic activity in mice. Here, we evaluated the potential for DENV-1 to escape neutralization by DENV1-E106. A single mutation in domain III of the envelope protein (T329A) emerged, which conferred resistance to DENV1-E106. However, the T329A variant virus had differing phenotypes in vitro and in vivo with attenuation in cell culture yet increased infectivity in Aedes aegypti mosquitoes. Mice infected with this T329A variant still were protected against lethal infection by DENV1-E106 even though much of the neutralizing activity was lost. This study reveals the complex dynamics of neutralization escape of an inhibitory MAb against DENV, and suggests that evaluation of therapeutic MAbs requires detailed investigation in relevant hosts.

KW - Antibody

KW - Dengue virus

KW - Escape

KW - Humanization

KW - Mice

KW - Mosquito

KW - Neutralization

KW - Pathogenesis

KW - Therapy

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JO - Virology

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ER -

Complex phenotypes in mosquitoes and mice associated with neutralization escape of a Dengue virus type 1 monoclonal antibody

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