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Phylogenetically Mapping the Evolution of the Zika Virus as It Spread Across the World

With the help of Robert Malone, MD, MS, and Jane Homan, PhD, BVMS, MVSC, and others from Atheric Pharmaceutical and ioGenetics, we identified a set of mutated viral sequences encoding predicted epitopes with homology to epitopes predicted for human neural development-related proteins: NDF4 (Neurogenic differentiation factor 4) and Nav2 (Neural navigator protein 2). Based on this observation, we raised the hypothesis that epitope mimicry may contribute to both congenital Zika syndrome as well as GBS. To better explain, one hallmark of epitope mimicry is when a patient’s proteins become a target of their own adaptive immune response (autoimmunity) after they have been infected by a pathogen, which expresses antigenic proteins with similarities to proteins that are normally produced by the patient’s own cells. Clinical autoimmunity can occur when virus proteins are similar to human proteins; antibodies produced to fight the virus can end up fighting not only the virus but also the human host. 
By using computer software tools to predict and compare Zika viral B cell epitopes likely to be recognized by the human immune system, identifying which of these epitopes corresponded to viral genetic changes during evolution and spread across the Pacific to Brazil, and then comparing these mutated epitopes to the entire predicted human B epitope proteome, we were able to identify two sets of mutated sequences (with homology to human proteins NDF4 and NAV2) which were specific to the evolving Asian-Pacific-American strain. This is important because it may help explain a change of behavior of the disease consequent to changes in computer-predicted B epitopes. Human neurogenic differentiation factor 4 (NeuroD4 or NDF4 UniProtKB —Q9HD90) is a basic helix-loop-helix (bHLH) transcription factor that is involved in neurogenesis and control of neuronal differentiation. Neural navigator protein 2 (NAV2 UniProtKB—Q8IVL1), a voltage gated sodium channel, is also involved in neuronal development, specifically in the development of different sensory organs. NAV2 is expressed in lung, heart, dorsal root ganglia, and Schwann cells in the peripheral nervous system, and in the central nervous system expression is concentrated in the circumventricular organs involved in body-fluid homeostasis. Among other activities, NAV2 affects cell migration and cytoskeletal functions by participating in regulation of microtubule dynamics. Epitope mimics present in Zika may act directly to interfere with cellular targets of these proteins, or may interact indirectly by eliciting autoimmune responses.
In our analysis, we also evaluated the structure of the Zika virus untranslated regions (UTR’s), which are important regulatory sequences located next to the coding sequence of the viral polyprotein. These sequences control both Zika virus replication and protein expression. By evaluating the pattern of genetic changes in the Zika genome as it crossed the Pacific, we identified conserved mutations which predict significant changes in both of these regulatory regions. Within the upstream sequences (5’UTR), one particular change we found was in the sequence flanking part of the Zika genome coding for the start of the Zika polyprotein.

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