ReviewPorcine circoviruses—Small but powerful
Section snippets
The virus and the disease
Porcine circoviruses belong to the genus Circovirus of the family Circoviridae, which comprises porcine viruses as Porcine circovirus type 1 (PCV1) and type 2 (PCV2) but also avian viruses as Psittacine beak and feather disease virus (BFDV), Pigeon circovirus (PiCV), Canary circovirus (CaCV) and Goose circovirus (GoCV) (Todd et al., 2005). Typical for all circoviruses is the single-stranded (ss) and circular DNA genome with a rather small size (1759–2319 nts) and the non-enveloped spherical
The viral genome
PCVs contain a circular ssDNA molecule with a size of 1759 in case of PCV1 and 1768 for PCV2. They are the smallest mammalian viruses yet known and encode only two major open reading frames, rep and cap, which perform the two most elementary functions of a virus, copying and the successive packaging of the viral genome. Circoviruses can therefore be regarded as a fascinating paradigm not only for induction of a complex pathogenesis but also for the reduction of the molecular equipment to the
The viral proteins
Two major ORFs are encoded by the genomes of PCV1 and PCV2 (Fig. 1): The largest ORF of the ambisense-organized circoviruses is located on the viral plus-strand (rep gene or ORF1). From ORF1 two proteins are expressed, which are both necessary for viral replication. Rep and Rep′ are produced from differentially spliced transcripts. The Rep protein is translated from the full-length transcript (PCV1: 312 aa; PCV2: 314 aa); a spliced transcript encodes truncated and C-terminal frame-shifted Rep′
PCV transcription
The start of the rep transcript of PCV1 has been mapped to nucleotide 767 ± 10. The promoter of rep, Prep, overlaps the origin of replication (nucleotides 640–796). Prep is negatively regulated by the Rep protein, which binds to hexamers H1 and H2. Interestingly, Rep′ also binds to H1/H2, but does not repress the activity of Prep. Binding of Rep and Rep′ to these sequence elements is also an essential prerequisite for initiation of replication. Since mutagenesis of H1/H2 decreases but does not
Virus import
PCVs are the smallest viruses that autonomously replicate in mammalian cells. In vivo, viral DNA and antigens are found in monocytic, epithelial and endothelial cells, but no substantial replication was identified in monocytic cells. In contrast, replication of PCV2 infection was detected in the endothelial cell line PEDSV.15, aortic endothelial cells, gut epithelial cells, and fibrocytes by an increase in the levels of Cap and Rep protein (Steiner et al., 2008). Interestingly, variations in
Replication of PCV
Upon infection, the viral ssDNA genome is converted by host cell factors into a dsDNA replicative form that serves as template for viral DNA replication (Fig. 2). The origin of replication is located within the non-coding region between the ORFs of rep and cap and overlaps with the promoter of the rep gene. A characteristic nonanucleotide sequence (5′-(A/T)AGTATTAC-3′ in PCV2 and PCV1, respectively) is conserved in all circoviruses and flanked by an inverted repeat (palindrome) of 11
Host–virus interaction
Due to their small genome size and highly limited coding capacity, the life cycle of PCV relies predominantly on host cell factors. Recently, several porcine proteins interacting with the viral proteins Rep/Rep′, Cap and the ORF3 protein were identified either by an yeast or a bacteria-based two-hybrid assay (Finsterbusch et al., 2009, Liu et al., 2007, Timmusk et al., 2006). Almost all interaction partners (summarized in Table 1) are annotated in the literature as proteins with multiple
Conclusion
After more than one decade of research addressing the molecular biology of PCV1 and PCV2, many questions concerning these two viruses are not yet answered. Although we have caught a first glimpse on the entry of PCVs into the cells, we do not know yet where the virus is assembled and how it is exported from the cell. Moreover, one would like to obtain more information about the virus–host interaction and the processes that lead to the onset of the disease. Therefore, we have to sort out, which
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