Research Development Foundation

Other

Arbovax, Inc.

Dennis T Brown

Racquel Hernandez

Raquel Hernandez

Katherine M Smith

Malcolm E Thomas

Kavita Nanda

Methods and compositions concerning mutant flaviviruses with host range mutations. In some embodiments the invention concerns nucleotide sequences that encode mutant flavivirus proteins. Viruses comprising these sequences that display reduced replication in mammalian cells are provided. In further aspects of the invention, flavivirus vaccine compositions are provided. In another embodiment the invention provides methods for vaccination against flavivirus infection.

Flavivirus host range mutations and uses thereof

Novel attenuating deletions of Chikungunya virus E2 polypeptides are provided as are attenuated viruses comprising the deletions. Also provided are immunogenic compositions comprising the attenuated viruses and methods of producing such viruses in cells (such as insect cells). Viruses of the embodiments can be used for immunization of animals to provide protection from the pathogenic effects of Chikungunya virus infection.

Attenuated Chikungunya virus

Methods and compositions concerning mutant flaviviruses with host-range phenotypes are provided. Nucleotide sequences that encode mutant flavivirus proteins are also provided. In certain aspects, viruses comprising these sequences display reduced replication in mammalian cells. In further aspects of the invention, flavivirus vaccine compositions and methods for vaccination against flavivirus infection are provided.

Flavivirus host-range mutations and uses thereof

Cleavage site for the protease furin is inserted between domains of a membrane glycoprotein. Upon cleavage by furin in the trans-Golgi network, the protein is separated into individual membrane-free domain that retains its native conformation. This protocol can be used to produce virus membrane protein domains for structural analysis and for trials as vaccines.

Insertion of furin protease cleavage sites in membrane proteins and uses thereof

The present invention is directed to genetically engineered, membrane-enveloped viruses with deletion mutations in the protein transmembrane domains. Also provided are viral vaccines based on the engineered viruses, methods of producing and using such vaccines.

Membrane virus host range mutations and their uses as vaccine substrates

The present invention is directed toward genetically-engineered, membrane-enveloped Alphaviruses, Flaviviruses, and Bunyaviruses containing modified viral transmembrane envelope glycoproteins (e.g., E2, E1, E, and G) and bearing altered host-range phenotypes that enables the viruses to replicate efficiently in insect cells, but not mammalian cells. The strategy for production of these mutations is based on the fact that unlike mammalian cell membranes, the membranes of insect cells contain no cholesterol and are thus thinner than mammalian membranes. Many membrane-coated viruses have membrane glycoproteins on their surface which are responsible for identifying and infecting target cells. These membrane glycoproteins have hydrophobic membrane-spanning domains which anchor the proteins in the membrane bilayer. The membrane-spanning domains of these transmembrane proteins must be long enough to reach from one side of the bilayer to the other in order to hold the proteins in the membrane. The transmembrane envelope glycoproteins have been modified by introducing deletions into the membrane spanning domain, said deletions resulting in a modified envelope glycoprotein that is capable of spanning insect cell membranes, but not mammalian cell membranes, and an altered host-range phenotype that enables the virus to infect and produce progeny virus in insect cells, and to infect, but not produce progeny virus, in mammalian cells.

Genetically-engineered alphaviruses, flaviviruses, and bunyaviruses with modified envelope transmembrane glycoproteins and altered host-range phenotype

The vaccines and methods of the present invention are based on deletion mutations in the protein transmembrane domains of membrane-enveloped viruses. The strategy for production of these mutations is based on the fact that unlike mammalian cell membranes, the membranes of insect cells contain no cholesterol; thus are thinner than mammalian membranes. Many membrane-coated viruses have membrane glycoproteins on their surface which are responsible for identifying and infecting target cells. These membrane glycoproteins have hydrophobic membrane-spanning domains which anchor the proteins in the membrane bilayer. The membrane-spanning domains of these transmembrane proteins must be long enough to reach from one side of the bilayer to the other in order to hold the proteins in the membrane. Provided is a vaccine, a method of producing this vaccine, and a method of using this vaccine, based on the differences between membranes of viruses replicated in invertebrates and membranes of viruses replicated in vertebrates.

Genetically-engineered sindbis virus with modified E2 Glycoprotein and altered host-range phenotype

The present invention provides a novel isolated and purified protein that is produced by Aedes albopictus L4.4 cells, having a molecular weight of 55 kDa of SDS-PAGE, is associated with lysosomal membranes and induces an anti-viral state. This anti-viral state is characterized by a total block of virus RNA synthesis with no effect of cell macromolecular synthesis. Also provided are various methods of using this novel protein or the gene encoding this protein.

Protein from albus albopictus cells and method for its use

The present invention provides a composition of matter, comprising a non-infectious, mutated virus suitable for use in preparing a vaccine. A plasmid adapted for expression in a recombinant cell comprising DNA encoding non-infectious mutated virus protein and regulatory elements necessary for expression of said DNA in the cell. Also provided are methods of inhibiting the spread of infection of a virus comprising the step of contacting said virus with a compound that inhibits thiol-reductase/protein disulfide isomerase activity in said virus.

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Raleigh, NC, United States of America

Dennis T Brown