Viral replication, from entry into a cell to expression of viral genes and the exit of progeny virus is dependant on functional interactions between viral and cell proteins and nucleic acids. Receptor binding and subsequent cell-mediated internalization or disassembly are the initial steps in virus replication. Cell surface molecules that participate in this process are the primary determinants of virus tissue tropism. The host range and tissue tropism of a virus is determined primarily by the presence of specific receptors on target cells which are recognized by viral proteins.
Adenoviruses and enteroviruses are common human pathogens. The genus Enterovirus comprises polioviruses, Coxsackie group A and B viruses, ECHO viruses and several unnamed enteroviruses. Enteroviruses are non-enveloped viruses that contain a single-stranded RNA genome which acts as an mRNA directing the synthesis of a single polyprotein. This polyprotein is subsequently processed by virus-encoded proteases to produce the structural capsid proteins and the non-structural proteins that are necessary for viral RNA replication. The viruses in the Adenoviridae family contain double-stranded linear DNA which replicates in the cell nucleus. Replication is semiconservative with each strand being elongated continuously without Okazaki intermediates. The viral origin of replication is located in the termini of the viral genome. Two types of replication are thought to occur. In type I, strand elongation occurs from duplex DNA with strand displacement. In type II replication occurs from a single stranded template possibly a panhandle type molecule. Because the template is linear, not circular, priming of synthesis occurs by covalent attachment of a nucleotide to the terminal protein.
A depression on the coxsackievirus surface is believed to be the site for receptor attachment. In contrast, adenovirus attachment to cells is mediated by globular knob domains of fiber proteins projecting from the adenoviral capsid. Despite these structural differences, coxsackievirus B3 and adenovirus 2 were found more than twenty years ago to compete for a HeLa cell attachment site. More recently, a 64-kDA glycoprotein was isolated from virus-sensitive mouse cells and its sequence was used to identify a human homolog. Both the human and mouse proteins were subsequently shown to mediate coxsackievirus and adenovirus attachment in cells and tissues of mouse and human origin (Henry, L. J. et al. (1994) J. Virol. 68:5239-5246; Lonberg-Holm, K. et al. (1976) Nature 259:679; and Tomko, R. P. et al. (1997) Proc. Natl. Acad. Sci. 94:3352-3356).
During infection, viruses induce a number of alterations in metabolic functions and morphological structures of the cell, most of which facilitate viral replication. These include inhibition of host cell protein and RNA synthesis, stimulation of lipid synthesis and inhibition of vesicular protein transport. The pathological effects of viral infections are determined by the alterations in cellular pathways, tissue types susceptable to infection and routes by which the virus can spread through the body. Although adenovirus and coxsackievirus share a common receptor they do not share the same host and tissue range. The adenovirus primarily infects the lungs and intestines whereas the coxsackievirus infects a variety of organs including the brain, heart, pancreas, and intestines. Coxsackievirus is the enterovirus most frequently involved in human myocarditis, dilated cardiomyopathy, meningoencephalitis and acute pancreatitis. Coxsackievirus B4 can induce autoimmune Type 1 diabetes by acting as a triggering agent in the generation of viral antigen-specific cytotoxic T cells which cross-react with beta cell-specific autoantigens. Specific adenovirus serotypes are associated with upper respiratory tract infections, pneumonia, conjunctivitis, and gastroenteritis. Adenovirus vectors have been used as vehicles for in vivo gene transfer to specific cell types by the deletion of the E1 region, resulting in replication deficient vectors (Andreoletti, L. et al. (1997) J. Med. Virol. 52:121-127; Yoon, J. W. (1992) Diabete Metab. 18:378-386).
The discovery of a new viral receptor protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of cancer, inflammation, and viral disorders.