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PMID: 16415011 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Antibodies against West Nile Virus nonstructural protein NS1 prevent lethal infection through Fc gamma receptor-dependent and -independent mechanisms.

Journal of virology ·Vol. 80 ·No. 3 ·2006-02-00 ·Pages 1340-51

Chung KM, Nybakken GE, Thompson BS, Engle MJ, Marri A, Fremont DH, Diamond MS

Abstract

The flavivirus nonstructural protein NS1 is a highly conserved secreted glycoprotein that does not package with the virion. Immunization with NS1 elicits a protective immune response against yellow fever, dengue, and tick-borne encephalitis flaviviruses through poorly defined mechanisms. In this study, we purified a recombinant, secreted form of West Nile virus (WNV) NS1 glycoprotein from baculovirus-infected insect cells and generated 22 new NS1-specific monoclonal antibodies (MAbs). By performing competitive binding assays and expressing truncated NS1 proteins on the surface of yeast (Saccharomyces cerevisiae) and in bacteria, we mapped 21 of the newly generated MAbs to three NS1 fragments. Prophylaxis of C57BL/6 mice with any of four MAbs (10NS1, 14NS1, 16NS1, and 17NS1) strongly protected against lethal WNV infection (75 to 95% survival, respectively) compared to saline-treated controls (17% survival). In contrast, other anti-NS1 MAbs of the same isotype provided no significant protection. Notably, 14NS1 and 16NS1 also demonstrated marked efficacy as postexposure therapy, even when administered as a single dose 4 days after infection. Virologic analysis showed that 17NS1 protects at an early stage in infection through a C1q-independent and Fc gamma receptor-dependent pathway. Interestingly, 14NS1, which maps to a distinct region on NS1, protected through a C1q- and Fc gamma receptor-independent mechanism. Overall, our data suggest that distinct regions of NS1 can elicit protective humoral immunity against WNV through different mechanisms.

MeSH Terms
Aedes Animals Antibodies, Monoclonal/pharmacology Antibodies, Viral/administration & dosage Antigens, Viral/genetics Base Sequence Cell Line Cricetinae DNA, Viral/genetics Epitope Mapping Mice Mice, Inbred C57BL Receptors, IgG/metabolism Recombinant Proteins/genetics,immunology Viral Nonstructural Proteins/genetics,immunology West Nile Fever/immunology,prevention & control,therapy West Nile virus/genetics,immunology,pathogenicity
Chemicals
Antibodies, Monoclonal Antibodies, Viral Antigens, Viral DNA, Viral NS1 protein, Flavivirus Receptors, IgG Recombinant Proteins Viral Nonstructural Proteins
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Chung Kyung Min
Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, Campus Box 8051, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Nybakken Grant E
Thompson Bruce S
Engle Michael J
Marri Anantha
Fremont Daved H
Diamond Michael S
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/JVI.80.3.1340-1351.2006
Published
2006-02-00
Pages
1340-51
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC1346945
Subset
IM
Grants
NIAID NIH HHS · U01 AI061373 · United States
NIAID NIH HHS · U54 AI057160 · United States
NIAID NIH HHS · U01 AI 61373 · United States
NIAID NIH HHS · U54 AI 57160 · United States
External Links
PubMed source DOI: 10.1128/JVI.80.3.1340-1351.2006 PMC Full Text View journal details
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