Rabbit haemorrhagic disease (RHD) and rabbit haemorrhagic disease virus (RHDV): a review

Abstract

Rabbit haemorrhagic disease virus (RHDV) is a calicivirus of the genus Lagovirus that causes rabbit haemorrhagic disease (RHD) in adult European rabbits (Oryctolagus cuniculus). First described in China in 1984, the virus rapidly spread worldwide and is nowadays considered as endemic in several countries. In Australia and New Zealand where rabbits are pests, RHDV was purposely introduced for rabbit biocontrol. Factors that may have precipitated RHD emergence remain unclear, but non-pathogenic strains seem to pre-date the appearance of the pathogenic strains suggesting a key role for the comprehension of the virus origins. All pathogenic strains are classified within one single serotype, but two subtypes are recognised, RHDV and RHDVa. RHD causes high mortality in both domestic and wild adult animals, with individuals succumbing between 48-72 h post-infection. No other species has been reported to be fatally susceptible to RHD. The disease is characterised by acute necrotising hepatitis, but haemorrhages may also be found in other organs, in particular the lungs, heart, and kidneys due to disseminated intravascular coagulation. Resistance to the disease might be explained in part by genetically determined absence or weak expression of attachment factors, but humoral immunity is also important. Disease control in rabbitries relies mainly on vaccination and biosecurity measures. Such measures are difficult to be implemented in wild populations. More recent research has indicated that RHDV might be used as a molecular tool for therapeutic applications. Although the study of RHDV and RHD has been hampered by the lack of an appropriate cell culture system for the virus, several aspects of the replication, epizootology, epidemiology and evolution have been disclosed. This review provides a broad coverage and description of the current knowledge on the disease and the virus.

Figure 1

Genomic organization of RHDV. The genome of RHDV is composed of two narrowly overlapping ORFs, ORF1 and ORF2. ORF1 codes for a polyprotein that is cleaved by the virus-encoded trypsin-like cysteine protease (arrowheads) and originates the major structural protein for the capsid (VP60) and the non-structural proteins p16, p23, helicase, p29, VPg, protease and RdRp. ORF2 codes for a minor structural protein, VP10. A subgenomic mRNA encoding both the structural proteins VP60 and VP10 can also be found in viral particles. Both the genomic and subgenomic RNA are polyadenylated at their 3'end and have the virus-encoded protein, VPg, covalently attached to their 5' end.

Figure 2

The replication cycle of caliciviruses. After attachment to the cellular receptor, the virion is internalised into the cell (step 1). Uncoating of the viral genome (step 2) is followed by translation of the polyprotein precursor (step 3) and co-translational processing releasing the non-structural proteins (step 4). These proteins assemble in a replication complex (step 5) that synthesises the antigenomic RNA (step 6), being itself used as a template for synthesis of the genomic RNA (step 7). The newly synthesized genomic RNA is translated as a polyprotein precursor (step 3) or is used for packaging in the assembled viral protein core (step 10). The antigenomic RNA is also the template for synthesis of subgenomic RNA (step 8). The subgenomic RNA is translated as structural proteins, VP60 and VP10 (step 9) and in lagoviruses, VP60 is also released from the polyprotein precursor after processing by the viral protease. At a still not defined time in the virus life cycle, assembly of the structural proteins as well as packaging of the genomic RNA occurs (step 10), followed by release of the mature virion from the cell (step 11). Reprinted from Antiviral Research, 87, Rohayem J, Bergmann M, Gebhardt J, Gould E, Tucker P, Mattevi A, Unge T, Hilgenfeld R, Neyts J, Antiviral strategies to control calicivirus infections, 167, 2010, with permission from Elsevier.

Figure 3

Schematic biosynthesis of the HBGA ABH and Lewis. Several transferase enzymes (boxed) are involved in the addition of relevant monosaccharides (in bold) to synthesise the ABH and Lewis ligands in a variety of tissues. Gal, Galactose; Glc, Glucose; GalNAc, N-Acetylgalactosamine; GlcNAc, N-Acetylglucosamine; Fuc, Fucose. With kind permission from Springer Science + Business Media: Glycoconjugate journal, Norwalk virus-like particles bind specifically to A, H and difucosylated Lewis but not to B histo-blood group active glycosphingolipids, 26(9), 2009, 1172, Nilsson J, Rydell GE, Le Pendu J, Larson G, Figure 1 (the figure includes minor alterations).

Figure 4

Phylogenetic relationships between the RHDV genogroups G1-G6 and the Italian non-pathogenic strain RCV. The tree was obtained using the neighbour-joining method and using nucleotide sequences from RHDV strains isolated worldwide. Bootstrap values greater than 50% are presented at the nodes. RCV was used as outgroup to root the tree. With kind permission from Springer Science + Business Media: Archives of Virology, Phylogenetic analysis of rabbit haemorrhagic disease virus in France between 1993 and 2000, and the characterisation of RHDV antigenic variants, 148(1), 2003, 72, Le Gall-Recule G, Zwingelstein F, Laurent S, de Boisseson C, Portejoie Y, Rasschaert D, Figure 2 (the figure includes minor alterations).