The use of antibodies that neutralize infection at a post-attachment step for the development of innovative immunotherapeutic strategies exemplified for selective destruction of Zika-infected human cells.

Abstract

Zika virus (ZIKV) is a flavivirus that is responsible for the current epidemic in Brazil and the Americas. It is transmitted to humans by the principle mosquito species Aedes aegypti, characterized by its remarkable ability to rapidly adapt to changing environments allowing them to bred in urban areas, flourishing in impoverished and crowded areas with no piped water and poorly collected garbage. ZIKV has been causally associated with fetal microcephaly, intrauterine growth restriction, and other birth defects in both humans and mice. Effective antiviral drugs are not yet available, posing an urgent medical need in particular for emergency cases. The ZIKV genome consists of a single-stranded positive sense RNA molecule with 10794 kb of length with 2 flanking non-coding regions (52 and 32 NCR) and a single long open reading frame encoding a polyprotein: 52-C-prM-E-NS1-NS2A-NS2B-NS3-NS4A-NS4B-NS5-32 that is cleaved into capsid (C), precursor of membrane (prM), envelope (E) and seven non-structural proteins (NS) (Figure 1).The E protein (H53 kDa) is the major virion surface protein being involved in various aspects of the viral cycle, mediating binding and membrane fusion. We intend to identify antibodies able to neutralize infectivity at a post-attachment step. The antibody-secreting cells corresponding to the antibodies of interest will have their variable genes sequenced. Recombinant antibody technologies would be used in collaboration with the group of Prof. Barth (UCT, South Africa) to select and engineer antibody fragments specific to the relevant epitopes. Prof. Barth has a track record on the generation of knowledge based recombinant immunodiagnostics and immunotherapeutics especially for proliferative diseases. This collaboration project would allow to rely on this expertise and to translate it to specific detection and elimination of infected cells. The most promising recombinant antibodies identified would be further modified by protein engineering to provide ZIKV specific next generation immunodiagnostics and therapeutics. General applicability of the recombinant antibody technologies as well as cross-reactivity, and mechanistic similarities of epitopes would in the future allow to extend the methodology to other flaviruses in particular (e.g. SLEV, WNV, EOCV, etc.) and arboviruses (e.g. alphaviruses and bunyaviruses) in general. (AU)