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Title: Chikungunya virus neutralization antigens and direct cell-to-cell transmission are revealed by human antibody-escape mutants
Authors: Lee C.Y.
Kam Y.-W.
Fric J.
Malleret B.
Koh E.G.L. 
Prakash C.
Huang W.
Lee W.W.L.
Lin C.
Lin R.T.P. 
Renia L.
Wang C.-I.
Ng L.F.P. 
Warter L.
Keywords: neutralizing antibody
immunoglobulin M
monoclonal antibody
neutralizing antibody
virus antibody
virus antigen
virus protein
Chikungunya alphavirus
controlled study
virus cell interaction
virus mutation
virus neutralization
virus resistance
virus transmission
Alphavirus infection
cell strain HEK293
chronic disease
disease transmission
immune evasion
mouse mutant
protein secondary structure
protein tertiary structure
Chikungunya virus
Alphavirus Infections
Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
Antigens, Viral
Chikungunya virus
Chronic Disease
HEK293 Cells
Immune Evasion
Immunoglobulin M
Mice, Knockout
Protein Structure, Secondary
Protein Structure, Tertiary
Viral Proteins
Issue Date: 2011
Citation: Lee C.Y., Kam Y.-W., Fric J., Malleret B., Koh E.G.L., Prakash C., Huang W., Lee W.W.L., Lin C., Lin R.T.P., Renia L., Wang C.-I., Ng L.F.P., Warter L. (2011). Chikungunya virus neutralization antigens and direct cell-to-cell transmission are revealed by human antibody-escape mutants. PLoS Pathogens 7 (12) : e1002390. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: Chikungunya virus (CHIKV) is an alphavirus responsible for numerous epidemics throughout Africa and Asia, causing infectious arthritis and reportedly linked with fatal infections in newborns and elderly. Previous studies in animal models indicate that humoral immunity can protect against CHIKV infection, but despite the potential efficacy of B-cell-driven intervention strategies, there are no virus-specific vaccines or therapies currently available. In addition, CHIKV has been reported to elicit long-lasting virus-specific IgM in humans, and to establish long-term persistence in non-human primates, suggesting that the virus might evade immune defenses to establish chronic infections in man. However, the mechanisms of immune evasion potentially employed by CHIKV remain uncharacterized. We previously described two human monoclonal antibodies that potently neutralize CHIKV infection. In the current report, we have characterized CHIKV mutants that escape antibody-dependent neutralization to identify the CHIKV E2 domain B and fusion loop "groove" as the primary determinants of CHIKV interaction with these antibodies. Furthermore, for the first time, we have also demonstrated direct CHIKV cell-to-cell transmission, as a mechanism that involves the E2 domain A and that is associated with viral resistance to antibody-dependent neutralization. Identification of CHIKV sub-domains that are associated with human protective immunity, will pave the way for the development of CHIKV-specific sub-domain vaccination strategies. Moreover, the clear demonstration of CHIKV cell-to-cell transmission and its possible role in the establishment of CHIKV persistence, will also inform the development of future anti-viral interventions. These data shed new light on CHIKV-host interactions that will help to combat human CHIKV infection and inform future studies of CHIKV pathogenesis. © 2011 Lee et al.
Source Title: PLoS Pathogens
ISSN: 15537366
DOI: 10.1371/journal.ppat.1002390
Rights: Attribution 4.0 International
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