Parechoviruses

Until recently, the family Picornaviridae consisted of five established genera (36). Enteroviruses, rhinoviruses, and hepatoviruses include human pathogens; foot-and-mouth disease viruses of ungulates are the most important aphthoviruses; and cardioviruses are found mainly in rodents (48). Following the early studies of Loeffler and Frosch on foot-and-mouth disease viruses (32), work on enteroviruses started in the early years of this century, when Landsteiner and Popper demonstrated, by injection of a filtrate into monkeys, that poliomyelitis is caused by viruses (31). However, it was 40 years before a new, related virus group was discovered (11). These were the coxsackieviruses, which characteristically could induce disease in newborn mice. Following the introduction of tissue culture systems (14) for virus propagation, several viruses which shared physicochemical properties (solvent-resistant, acid-stable particles) with polioand coxsackieviruses, but grew exclusively in cell culture, were isolated. These were called ECHO (enteric, cytopathogenic, human, orphan) viruses (9). The three subgroups, plus the new enterovirus types 68 to 71, include more than 60 serotypes and, together with several simian, bovine, and porcine strains, comprise the Enterovirus genus (25). However, a wide range of evidence, detailed below, shows that two echoviruses have distinct biological and molecular properties. These, echoviruses 22 and 23, have recently been assigned to a sixth picornavirus genus, Parechovirus, and have been renamed human parechovirus 1 and 2 (HPEV1 and HPEV2), respectively (29). Here we review how parechoviruses relate to other members of the Picornaviridae family. Previously studied picornaviruses have a single-stranded RNA genome of positive polarity, 7,100 to 8,500 nucleotides long, which is packaged into an icosahedral capsid made up of 60 copies of each of the capsid proteins VP1 through VP4 (48, 57). Genomic RNA is modified by the covalent attachment of a small protein (VPg; 20 to 25 amino acids) to the 59 terminus. The genome can be considered to have four distinct domains. A 59 untranslated region (59UTR) precedes a single open reading frame, downstream of which there is a 39UTR and a poly(A) tract. Ten, 11, or 12 proteins are encoded by different picornaviruses as shown in Fig. 1. The single polyprotein encoded by the genome is processed by a cascade of proteolytic events, instigated by virus-encoded enzymes, to give precursor molecules and then the final discrete proteins (40, 50). In several cases, the precursors themselves have important functional roles in virus replication. For instance, while the majority of processing events are brought about by 3C, cleavages in the capsid region appear to require 3CD, the precursor of 3C and 3D. Functions have been ascribed to most of the nonstructural proteins. In addition to its involvement with 3C in processing, 3D possesses the RNA-dependent RNA polymerase activity needed for replication. Some of the other proteins are also involved in the RNA replication complex, including 3A, 3B (VPg), and 2C (48). In picornaviruses other than parechoviruses, four capsid proteins are observed. These are named 1A, 1B, 1C, and 1D in the systematic nomenclature based on genomic location, but they are commonly designated VP4, VP2, VP3, and VP1, respectively. The external polypeptides, VP1 to VP3, share the same core structure, an eight-stranded antiparallel b-barrel, and are of similar size, while VP4 is internal and is much smaller (47). Assembly involves VP1, VP3, and the precursor VP0. Cleavage of VP0 into VP4 and VP2, termed the maturation cleavage and brought about by an unknown mechanism, is the final assembly step and is associated with stabilization of the particle and acquisition of infectivity.