Antibody Dependent Enhancement of Zika Virus: It’s Complicated

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Antibodies elicited by other flaviviruses enhance Zika virus infection in vitro, but enhancement is not strictly correlated with binding affinity

Text by Scott Hensley and Elinor Willis

Zika viruses are circulating in parts of the world that are endemic for other flaviviruses. Recent studies suggest that cross-reactive antibodies elicited by other flaviviruses can enhance Zika virus replication in vitro.  It’s possible that antibodies targeting different regions of Zika virus might have different enhancing potentials.  To address this, we measured Zika virus binding and enhancing ability of a relatively large number of murine monoclonal antibodies elicited by exposure to Dengue virus or West Nile virus.

So, how did we get interested in studying Zika viruses?  Our lab studies how prior influenza virus infections shape antibody responses to antigenically distinct influenza virus strains.  We have found that the specificity of antibodies elicited by influenza viruses is affected by prior influenza virus exposures.  Subtle differences in influenza virus antibody specificity can have profound consequences since influenza viruses are constantly acquiring mutations that abrogate the binding of some antibodies, but not others. There are many parallels between influenza viruses and flaviviruses with regards to pre-existing immunity.  In the case of flaviviruses, antibodies elicited during a prior infection can bind to a second flavivirus and enhance viral uptake and immune recognition.

When we initiated our study, it was unknown whether antibodies elicited by other flaviviruses bound to Zika virus and enhanced viral replication.  Over the course of our studies, several groups published manuscripts showing that this indeed occurs.  So, we were confronted with a dilemma: do we abandon our studies because we were ‘scooped’ or was there anything new and interesting in our dataset?  Unlike published studies, we tested the enhancing potential of a large number of monoclonal antibodies.  This allowed us to address whether specificity affects antibody enhancing potential.  As some flavivirus gurus might have predicted, we found that the enhancing phenotype was very complicated. Different types of antibodies in our panel could enhance Zika virus infection and enhancement was not strictly correlated with relative binding affinity.

It is still not clear how our results relate to what is actually happening in vivo.  The situation in vivo is much more complicated since enhancement is likely affected by increases in viral replication as well as engagement of innate immune cells.  Recent studies indicate that antibodies against Dengue virus and West Nile virus can enhance Zika virus replication and pathogenesis in a mouse model.  However, other human studies suggest that antibodies elicited by Dengue viruses protect against Zika virus infection.  It will be interesting to tease out the specificities of antibodies involved in these different studies.

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Figure legend

(A) Monoclonal antibodies elicited by Dengue (green) or West Nile (red) viruses enhance Zika virus infection of K562 cells, a human erythroleukemic cell line that expresses Fc receptors. (B) Enhancement potential does not strictly correlate with relative binding, as measured by ELISA.

Introducing the authors


Elinor Willis (left) and Scott E. Hensley work at the Department of Microbiology, University of Pennsylvania.

About the research

Characterization of Zika virus binding and enhancement potential of a large panel of flavivirus murine monoclonal antibodies

Elinor Willis, Scott E. Hensley

Virology, Volume 508, August 2017, Pages 1–6