Abstract
Rift Valley fever (RVF) is a mosquito-borne zoonotic disease endemic to the African continent. RVF is characterized by high rate of abortions in ruminants and hemorrhagic fever, encephalitis, or blindness in humans. RVF is caused by the Rift Valley fever virus (RVFV: genus Phlebovirus, family Bunyaviridae). Vaccination is the only known effective strategy to prevent the disease, but there are no licensed RVF vaccines available for humans. A live-attenuated vaccine candidate derived from the wild-type pathogenic Egyptian ZH548 strain, MP-12, has been conditionally licensed for veterinary use in the U.S. MP-12 displays a temperature-sensitive (ts) phenotype and does not replicate at 41°C. The ts mutation limits viral replication at a specific body temperature and may lead to an attenuation of the virus. Here we will review well-characterized ts mutations for RNA viruses, and further discuss the potential in designing novel live-attenuated vaccines for RVF.
Highlights
Though the MP-12 vaccine is conditionally licensed for veterinary use in the U.S, a few studies indicated that the vaccine may cause abortions in pregnant ewes and mild hepatitis in calves (Hunter et al, 2002; Miller et al, 2015)
The Rift Valley fever virus (RVFV) T46 strain, which was isolated from Aedes taeniorhynchus that fed on ZH501-infected gerbils, predominantly produced small plaques, but was pathogenic in hamsters, without showing a ts phenotype
Little is known about the efficacy of Rift Valley fever (RVF) vaccines against aerosol challenge of pathogenic RVFV
Summary
Rift Valley fever virus encodes two non-structural proteins, NSs and NSm. Both proteins are dispensable for viral replication. NSs suppresses host general transcription by interrupting the assembly of transcription factor (TF) IIH, which is essential for the function of cellular RNA polymerase I or II (Le May et al, 2004; Kalveram et al, 2011; Kainulainen et al, 2014). RVFV NSs promotes the degradation of dsRNA-dependent protein kinase (PKR). PKR homodimers undergo autophosphorylation and phosphorylate eukaryotic initiation factor (eIF) 2α, which inhibits the initiation of cellular and viral translation. By promoting the degradation of PKR, RVFV can synthesize viral proteins without inducing significant eIF2α phosphorylation (Habjan et al, 2009; Ikegami et al, 2009). The S-segment encodes two open reading frames (ORF) for a nucleoprotein (N) and a non-structural protein (NSs) in an ambi-sense manner. The L-segment encodes a single ORF for the RNA-dependent RNA polymerase (L) protein. The complexes of Gn and Gc localize to the Golgi and trigger the assembly of RNP and L, and the budding of virions (Piper et al, 2011)
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