Classification

The member viruses of the family Circoviridae share some common virion and genome properties, but are ecologically, biologically, and antigenically quite distinct. Circoviruses are similar to plant geminiviruses and nanoviruses in terms of their genomic organization and replication strategy. It is speculated, therefore, that animal circoviruses may have originated from a plant nanovirus through host-switching and subsequent recombination with a mammalian virus. The family currently includes two genera (Circovirus, Gyrovirus). Porcine circovirus 1 is the type species of the genus Circovirus, members of which use an ambisense genome replication strategy with viral genes in different orientations. The genus Circovirus includes beak and feather disease virus, canary circovirus, goose circovirus, pigeon circovirus, duck circovirus, finch circovirus, gull circovirus, and porcine circoviruses 1 and 2. A recently described canine circovirus shares the same general properties of these circoviruses, as do many other avian circoviruses that are not yet classified taxonomically. Chicken anemia virus is the type member of the genus Gyrovirus, in which the viral genes are all in the same orientation. Additional genetically diverse gyroviruses have recently been identified in humans and chickens, although the biological and clinical significance of these novel gyroviruses is uncertain. The “Cyclovirus” sequences recently detected in feces from humans and chimpanzees may form an additional, previously unrecognized genus in the family Circoviridae.

Virion Properties

Circoviruses are all highly stable in the environment and, like parvoviruses, are notoriously difficult to inactivate, For example, they are not inactivated by heating at 60°C for 30 minutes, are highly resistant to many disinfectants, and may require long exposure even to efficacious chemical sterilizers.

Virus Replication

The receptors responsible for cellular attachment of circoviruses are not well characterized, but some circoviruses hemagglutinate erythrocytes and thus they are likely to bind to sialic acid residues on the cell surface. Porcine circovirus 2 utilizes heparin/heparan sulfate and chondroitin sulfate B glycosaminoglycans as general attachment receptors, which may explain why the virus exhibits broad tropism to multiple organs and tissues in pigs. Despite the ubiquitous nature of these receptors, however, cells of the monocyte/macrophage lineage are preferentially targeted. A specific entry receptor for porcine circovirus 2 has not been identified. Virus particles are taken up into cells by endocytosis, likely via clathrin-mediated endocytosis although the specific mechanisms also are not well understood. Porcine circovirus 2 is internalized by both mature and immature dendritic cells, including blood dendritic cells, plasmacytoid dendritic cells, and dendritic cell precursors, suggesting that a nonmacropinocytic uptake of the virus may be involved in virus entry. Epithelial cells are also major targets for porcine circovirus 2 in swine, and a dynamin- and cholesterol-independent but actin- and small GTPase-dependent pathway facilitates the entry and internalization of the virus into epithelial cells prior to replication.

After entry and localization of porcine circovirus 2 in endosomes, a serine protease is required for virus release from the endosome, which suggests that proteolytic cleavage of the capsid protein (Cap) occurs during the uncoating process. Viral DNA replication occurs in the nucleus of infected cells and requires cellular proteins and other components produced during the S phase of the cell cycle. Replication of the genome is believed to occur via a rolling circle that originates at a stem-loop structure. Three conserved rolling-circle replication motifs (RCR-I, RCR-II, and RCR-III) and a dNTP-binding motif are present within the replicase (Rep and Rep’) proteins of porcine circoviruses, and mutation of conserved motifs negatively affects virus replication. Three distinct proteins (VP1, VP2, and VP3) are produced during replication of chicken anemia virus. A 3-amino acid motif in VP1 is associated with rolling-circle replication. The phosphatase activity of VP2 is important, though not required, for virus replication, and VP3 is essential for completion of the virus’ life cycle.

A major feature of the circoviruses that determines their pathogenesis is the requirement for actively dividing cells to facilitate replication of their DNA, thus virus replication occurs in actively dividing cells in the tissues of young animals. Similarly, replication of porcine circovirus 2 in swine is enhanced during periods of immune stimulation that result in proliferation of lymphocytes in which the virus can replicate. Circoviruses typically cause persistent infections of their respective hosts, although the mechanisms responsible for establishing persistent infection are poorly understood as these viruses persist despite apparently robust host antiviral immune responses. In the case of chicken anemia virus, virus replication in the oviduct of chickens may be regulated by estrogen, and hence is differentially stimulated, particularly during egg laying, to allow more efficient vertical transmission. The apoptin protein of chicken anemia virus may itself cause destruction of infected lymphocytes, and hence promote a relative immune suppression that favors virus persistence.

Clinical Features and Epidemiology