Received 7/17/97, Accepted, 8/13/97

3. COXSACKIEVIRUSES - GENERAL FEATURES

Coxsackieviruses are enteroviruses belonging to the Picornaviridae family. The first reported coxsackievirus isolate came from the town of Coxsackie in upstate New York (1). These enteroviruses are further subdivided into two serogroups, A and B, which comprise 24 and 6 serotypes, respectively (2). Of the two serogroups, the group A viruses are associated with less severe clinical syndromes than the group B viruses. Hence, coxsackievirus research has focused predominantly on the group B viruses. The group B viruses have been implicated in a variety of human diseases such as pancreatitis, type I insulin-dependent diabetes mellitus, myocarditis, myositis, severe systemic disease in infants, aseptic meningitis and respiratory illnesses (3-7). The broad spectrum of diseases associated with the group B viruses reflects the existence of variants within a given serotype. Although there is a great deal of information on the biochemical, biophysical and genetic characteristics of the picornaviruses, the mechanisms by which these viruses cause disease are poorly understood.

Picornaviruses are among the smallest RNA viruses, with a diameter of 30 nm (reviewed in (7)). Of the picornaviruses, the most extensively studied is the polioviruses. The assumption is that the fundamental processes of viral replication are similar for all picornaviruses. The virion consists of a protein shell surrounding an RNA genome. Picornaviruses lack lipid envelopes. The protein shell contains four polypeptide chains or capsid proteins, VP1, VP2, VP3 and VP4 that form an icosahedron. The four capsid proteins assemble into a protomer, five of which are organized into a pentamer. Twelve pentamers assemble into an icosahedron around the RNA genome. The three-dimensional structures of several picornaviruses have been solved. The recently solved three-dimensional structure of CVB3 shows its relatedness to both the polioviruses and the rhinoviruses (8). (Information on the structure of picornaviruses may be obtained from the Picornavirus home page at http://www.iah.bbsrc.ac.uk/virus/Picornaviridae/). The enteroviral genome consists of a single-stranded RNA of positive polarity. The genomes of four group B coxsackieviruses (B1, B3, B4, B5) have been sequenced (9-12). Excluding the poly(A) tract, the genome of coxsackievirus B4 (CVB4) consists of 7395 nucleotides and is composed of a 5' untranslated region (UTR) of 743 nucleotides, a 3' UTR of 105 nucleotides and an open reading frame encoding a polyprotein of 2183 amino acids which is proteolytically cleaved to yield mature viral proteins (Figure 1) (10). The open reading frame is divided into three regions, P1, P2 and P3. The four capsid proteins, VP1 through VP4, are encoded within the P1 region while the non-structural proteins that are involved in viral replication are encoded within the P2 and P3 regions. Viral multiplication occurs entirely in the cytoplasm. Infection is initiated by the attachment of virus to specific cellular receptors which results in conformational changes in the virion, allowing viral RNA to be released into the cytoplasm. Viral RNA is translated into a polyprotein. In addition, viral RNA serves as a template for the synthesis of minus-strand RNA which is used as templates for the synthesis of new plus strands of RNA. Plus-strand RNA and capsid proteins assemble into progeny virions which are released by cell lysis.

Figure 1. Genotypes of recombinant, chimeric coxachieviruses. The top line depicts the structural organization of the viral genome (10). Mortality rates are from infected B10.T(6R) mice.

In humans, coxsackievirus infections have been linked to diseases of both the exocrine and endocrine pancreas i.e., pancreatitis and type I insulin-dependent diabetes mellitus (IDDM), respectively. Pancreatitis is characterized by inflammation, edema and necrosis of the exocrine pancreas. IDDM is an autoimmune disease that results from the destruction of insulin-producing beta cells within the endocrine pancreas, the islets of Langerhans. The data linking coxsackieviruses to these two pancreatic diseases is derived from epidemiological studies, case reports and animal models. This review is limited to a discussion of coxsackievirus infections and pancreatitis. The role of coxsackieviruses in diabetes has been the topic of a recent review (6).