Live attenuated nairovirus vaccines: targeted mutations in a recombinant virus

Lead Research Organisation: The Pirbright Institute
Department Name: UNLISTED

Abstract

The nairoviruses are a genus of tri-segmented negative stranded RNA viruses of the family Bunyaviridae. One member of the genus (CCHFV) causes a severe hemorrhagic disease in man and another (NSDV) causes a very similar disease in sheep and goats. As no animal model of hemorrhagic fever caused by this group of viruses exists, this project will set up a system to study NSDV as a model nairovirus. We will establish a system to rescue recombinant viruses from cloned cDNA copies of the virus segments. We will express the two core viral protein (N and L) in cells and study the effects of each on the host's interferon induction and action pathways. Much recent data has shown that viruses have a multitude of mechanisms to block the activation, or activity, of the interferons that form part of the innate immune response to infection. A virus that has had this ability deleted will be permanently attenuated in vivo and is likely to be a candidate vaccine. We will identify the viral protein that provides this functionality and modify it in such a way as to ablate that function. We will use the rescue system to create a virus that can no longer block the host interferon response. A suitably mutated protein sequence will be built into a recombinant virus and native and mutated viruses will be tested in animals for virulence and for stimulation of the immune response in the host. We will also study the unique protease-like motif in the amino-terminus of the virual polymerase protein, looking at the effects of protease inhibitors and mutations in this domain on virus growth and on host cell responses to infection.

Publications

10 25 50