Shortening of Zika virus CD-loop reduces neurovirulence while preserving antigenicity

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Dinnon III, Kenneth H.
- Affiliation: School of Medicine, Department of Microbiology and Immunology
Gallichotte, Emily N.
- Affiliation: School of Medicine, Department of Microbiology and Immunology
Fritch, Ethan
- Affiliation: School of Medicine, Department of Microbiology and Immunology
Menachery, Vineet D.
- Affiliation: School of Medicine, Department of Microbiology and Immunology
Baric, Ralph S.
- Affiliation: School of Medicine, Department of Microbiology and Immunology

Abstract

Zika virus (ZIKV) is a mosquito-borne positive sense RNA virus. Recently, ZIKV emerged into the Western hemisphere as a human health threat, with severe disease associated with developmental and neurological complications. The structural envelope protein of ZIKV and other neurotropic flaviviruses contains an extended CD-loop relative to non-neurotropic flaviviruses, and has been shown to augment ZIKV stability and pathogenesis. Here we show that shortening the CD-loop in ZIKV attenuates the virus in mice, by reducing the ability to invade and replicate in the central nervous system. The CD-loop mutation was genetically stable following infection in mice, though secondary site mutations arise adjacent to the CD-loop. Importantly, while shortening of the CD-loop attenuates the virus, the CD-loop mutant maintains antigenicity in immunocompetent mice, eliciting an antibody response that similarly neutralizes both the mutant and wildtype ZIKV. These findings suggest that the extended CD-loop in ZIKV is a determinant of neurotropism and may be a target in live-attenuated vaccine design, for not only ZIKV, but for other neurotropic flaviviruses.

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