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. 2015 Jan 20;6(1):e02227-14.
doi: 10.1128/mBio.02227-14.

Evaluation of the potential impact of Ebola virus genomic drift on the efficacy of sequence-based candidate therapeutics

Jeffrey R Kugelman  1 , Mariano Sanchez-Lockhart  1 , Kristian G Andersen  2 , Stephen Gire  2 , Daniel J Park  2 , Rachel Sealfon  3 , Aaron E Lin  2 , Shirlee Wohl  2 , Pardis C Sabeti  2 , Jens H Kuhn  4 , Gustavo F Palacios  5
Affiliations

Evaluation of the potential impact of Ebola virus genomic drift on the efficacy of sequence-based candidate therapeutics

Jeffrey R Kugelman et al. mBio. .

Abstract

Until recently, Ebola virus (EBOV) was a rarely encountered human pathogen that caused disease among small populations with extraordinarily high lethality. At the end of 2013, EBOV initiated an unprecedented disease outbreak in West Africa that is still ongoing and has already caused thousands of deaths. Recent studies revealed the genomic changes this particular EBOV variant undergoes over time during human-to-human transmission. Here we highlight the genomic changes that might negatively impact the efficacy of currently available EBOV sequence-based candidate therapeutics, such as small interfering RNAs (siRNAs), phosphorodiamidate morpholino oligomers (PMOs), and antibodies. Ten of the observed mutations modify the sequence of the binding sites of monoclonal antibody (MAb) 13F6, MAb 1H3, MAb 6D8, MAb 13C6, and siRNA EK-1, VP24, and VP35 targets and might influence the binding efficacy of the sequence-based therapeutics, suggesting that their efficacy should be reevaluated against the currently circulating strain.

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Figures

FIG 1
FIG 1
Mutation analysis of candidate therapeutic binding sites. An SNP table is combined with a heat map based on three categories: (i) mutation shown to be tolerated by the therapeutic (10), (ii) mutations that are within the binding region of the therapeutic but have not been tested (8–12, 15, 18, 19), and (iii) tolerated diversity between development strains. %EBOV-WA, percentage of genomes containing a change in the West African (WA) sequences of 2014 from EBOV/Kik-9510621.
FIG 2
FIG 2
EBOV therapeutic map. Each of the therapeutics was mapped onto the genome of EBOV/Kik-9510621 according to published binding information. Blue arrows represent the nine open reading frames conserved among all Ebola viruses. A graphic representation of the SNPs is above the genomic position scale. Red vertical bars denote nonsynonymous mutations, blue vertical bars represent synonymous mutations, and green vertical bars represent noncoding mutations.
See this image and copyright information in PMC

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