The molecular dynamics of feline coronaviruses Peter J.M. Rottier* Veterinary Faculty, Utrecht University, Department of Infectious Diseases and Immunology, Virology Unit, Yalelaan 1, 3584 CL Utrecht, The Netherlands Abstract Feline coronaviruses are widespread and come in different flavors. There are two main serotypes both of which occur in two pathotypes, the avirulent enteric viruses and the virulent, usually fatal peritonitis viruses, the latter in turn occurring either in a wet or exudative form or in a dry or proliferative form. In this paper a concise overview is given of the molecular features of these viruses. Special attention is given to the genetic dynamics of the viruses as these now allow us to begin to understand the origin of the different phenotypes, in particular the genesis of virulence during persistent infection. As discussed, the surprising new insights obtained over the last few years call for a critical reevaluation of strategies for protection. # 1999 Elsevier Science B.V. All rights reserved. Keywords: Feline coronavirus; Feline infectious peritonitis; Coronavirus persistence 1. Introduction The Utrecht group has been accumulating data on feline coronaviruses for more than two decades; Marian C. Horzinek started the work on feline infectious peritonitis in 1975, and with Raoul de Groot, Harry Vennema, Herman Egberink and Bart Haagmans our group has made major contributions on this topic. Arnold Herreweghs dissertation, based on five papers, is the last coherent addition to the subject (Herrewegh, 1997). Coronaviruses are positive-stranded RNA viruses, recently accommodated in the order Nidovirales. The family Coronaviridae includes the genera Coronavirus and Torovirus, whereas the Arteriviridae contains but a single genus (Arterivirus) so far. The viruses have been classified in the order Nidovirales mainly on the basis of two features: their genome organization and their replication strategy (for review, see de Vries et al., 1997). The organization of the genomes of the corona-, toro-, and arteriviruses is quite similar: they have a large open reading frame at the 5-end of their genome, which encodes the Veterinary Microbiology 69 (1999) 117125 * Tel: +31 302532462; fax: +31 302536723. 0378-1135/99/$ see front matter # 1999 Elsevier Science B.V. All rights reserved. PII: S0378-1135(99)00099-1 polymerase (Fig. 1). It is synthesized as a precursor protein, which is in part generated by ribosomal frameshifting and which is processed by proteolytic cleavages to generate the functional proteins. Further downstream from the polymerase gene there is a collection of open reading frames, amongst which the genes for the structural proteins are located, as well as genes of largely unknown function. There is some variation in the genetic make- up of coronaviruses, e.g., with respect to the hemagglutinin/esterase (HE) gene, which is lacking in feline viruses. The genes for the structural proteins are obviously present in all viruses, but again there are differences: thus toroviruses lack an E protein, which for coronaviruses is essential in the assembly process. The other common feature is the replication strategy, more specifically: the way these viruses make their proteins. The polymerase protein is translated from the genome, the incoming viral RNA. The other open reading frames are translated from subgenomic messenger RNAs that are generated by a specific mechanism of discontinuous transcription. Each mRNA of this collection is responsible for one protein by translation of the 5-most open reading frame. Coronaviruses can be grouped into three clusters on the basis of genetic comparisons (Table 1). We find the feline coronaviruses in Group 1, together with e.g., porcine transmissible gastroenteritis virus and canine coronavirus. The most prominent member of Group 2 is mouse hepatitis virus, also the coronavirus type species. Infectious bronchitis virus and its many variants constitute Group 3. Electron microscopically these viruses present a characteristic picture, with a corona surrounding the enveloped particle, a halo of very typical surface projections. Within the envelope resides the nucleocapsid, which harbors the plus-stranded huge RNA molecule of some 30 kb, the Fig. 1. Genome organization of feline coronavirus. The gene for the polymerase polyprotein is indicated (POLla and POLib). The genes for the structural proteins spike (S), envelope (E), membrane (M), and nucleocapsid (N) are shaded. Genes encoding proteins of unknown function are designated by numerals. Table 1 Division of coronavirusesa Group 1Group 2Group 3 CCVBCVIBV FIPVHCV OC43 HCVHEV PEDVMHV TGEV 229ETCV aExplanation of acronyms: bovine coronavirus: BCV; canine coronavirus: CCV; feline infectious peritonitis virus: FIPV; human coronavirus 229E: HCV 229E; human coronavirus 0C43: HCV 0C43; hemagglutinating encephalomyelitis virus: HEV; infectious bronchitis virus: IBV; mouse hepatitis virus: MHV; porcine epidemic diarr