BIOLOGY OF C CLUSTER COXSACKIEVIRUSES

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In this new application Dr. Wimmer proposes to examine a variety of different picornaviruses in the C cluster of coxsackievirus (C-CAV), which is the group that are defined on the basis of sequence similarities as containing poliovirus, and various coxsackieviruses, including CAV21 and CAV24. The overall objective of the proposal is to gain more information about those viruses, and also to develop new model systems from some of them. In these studies they will use their extensive knowledge and studies of poliovirus systems as a model for proposing the systems to be developed for the viruses to be studied here. There are a variety of different experiments proposed, and several different viruses will be examined in various parts of the proposed studies. During the course of the studies the investigators will make selections among the viruses in order to decide on the virus (es) to be studied in more detail. There are 4 specific aims. The first is to perform some very basic virological studies of the C-CAVs--but mainly on CAV21--to determine which of them can grow well in tissue culture, and then to study the growth characteristics and other general properties of the virion. Other studies will be of the antigenic properties of the virion, including the preparation and mapping of the neutralizing epitopes of the virus. The second specific aim is to define the genomic properties of the C-CAVs, including the preparation of full-length clones and infectious cDNAs of several of the viruses, in particular the Coxsackie A24 virus (CAV24), and the CAV24v that is a variant the causes hemorrhagic conjunctivitis. The sequences will also be used in studies of the evolutionary relationships between the various C-CAVs. Other studies would include the cell free de novo synthesis of CAV21, and various studies involving recombining genomic segments among the different C-CAVs in order to map their biological differences. The 3rd specific aim is to crystallize the capsid of one or more of those viruses, and then determine the structures of the virion by X-ray crystallography, in collaborative studies with Michael Rossmann and Richard Kuhn at Purdue University. The 4th specific goal is to define the interactions between the capsid and the receptors of those viruses, including ICAM-1 and DAF with CAV21a, and the relationships between CAV24 and CAV24v.