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Lymphocystis disease was the first clinical illness linked with an iridovirus. However, although clinical manifestations of infection (i.e., wart-like or tumor-like growths on the skin of infected fish) were first noted near the end of the 19th century, the specific etiological agent was not identified until nearly 100 years later. In contrast to the systemic infections seen with ranaviruses and megalocytiviruses, lymphocystivirus infections result in wart-like growths mainly on the skin of infected fish. These growths are composed of numerous greatly enlarged cells. Infected cells are commonly 100 μm in diameter and sometimes reach 1 mm, a 50,000-100,000 increase in cell volume. LCDV-infected cells display a thick hyaline capsule, a central enlarged nucleus, and prominent basophilic DNA cytoplasmic inclusions.
Particle size varies from 198 to 227 nm for lymphocystis disease virus 1 (LCDV1) and 200 nm for LCDV2. The icosahedral capsid may show a fringe of fibril-like external protrusions about 2.5 nm in length. The presence of capsid fibers may distinguish lymphocystiviruses from the two other genera of vertebrate iridoviruses.
Virions are heat labile. Infectivity is sensitive to treatment with ether or glycerol.
Reported genome sizes within the genus vary widely: LCDV1, 102.6 kbp; LCDV-C, 186 kbp, and LCDV-Sa, 209 kbp. The latter virus contains the largest genome among known vertebrate iridoviruses. A contour length measurement of 146 kbp for LCDV1 suggests a terminal redundancy of approximately 50%. Like other vertebrate iridovirids, the lymphocystivirus genome is highly methylated. 5-methylcytosine occurs at 74% of CpG dinucleotides resulting in an overall level of methylation of 22%. The complete DNA sequence is known for the three isolates indicated above and partial sequences are known for several others. Surprisingly, the G+C content, but not the methylation status, of the three fully-sequenced lymphocystiviruses is more like that of invertebrate iridoviruses rather than other vertebrate iridoviruses (Table 2.Iridoviridae). Furthermore, the published genome size of LCDV1 is much smaller than that of LCDV-C and LCDV-Sa. Whether this reflects critical biological differences between LCDV1 and LCDV-C and LCDV-Sa, or whether it reflects a sequencing error, perhaps due to the presence of repeat regions, remains to be determined.
Little is known about the protein composition of lymphocystiviruses. The reported genome sizes are sufficient to encode between 108-183 proteins. BLAST analysis of predicted ORFs suggests that many putative gene products may be unique to the genus.
Genomic organization: The LCDV1 genome contains 108 largely non-overlapping ORFs, 38 of which show significant homology to proteins of known function. These 38 ORFs represent 43% of the coding capacity of the genome. The presence of a DNA methyltransferase and a methyl-sensitive restriction endonuclease with specificity for a CCGG target site may be indicative of a restriction-modification system capable of degrading host genomic DNA while protecting viral DNA by specific methylation. LCDV1 DNA contains numerous short direct, inverted and palindromic repetitive sequence elements.
The LCDV-C genome contains 178 non-overlapping ORFs, 103 of which are homologs to the corresponding ORFs of LCDV1 and 75 potential genes that were not found in LCDV1 or other iridovirids. Among these 75 genes, there are eight genes that contain conserved domains of cellular genes and 67 novel genes that do not show any signiﬁcant homology with the sequences in public databases. Although LCDV1 and LCDV-C possess 103 genes in common, their genomic organization (i.e. gene order) is markedly different. Furthermore, a large number of tandem and overlapping repeated sequences were observed in the LCDV-C genome.
LCDV-Sa contains 183 putative ORFs. BLASTp analysis found that 145 ORFs displayed significant similarity to other genes in the database. Of these 145, 129 best matched those in LCDV-C, 10 best matched LCDV1, two matched to ORFs within the SDDV genome and the remaining four best matched either fish (3 ORFs) or spider (1 ORF) genes.
Overall LCDV-Sa shared 55% identity to LCDV-C and 39% with LCDV1; LCDV1 and LCDV-C shared 42% identity to each other. Dot plot analysis of genomic co-linearity showed evidence of marked genomic rearrangements when compared to LCDV-C and almost complete lack of co-linearity with LCDV1. Based on genetic differences separating these isolates and the marked lack of genomic co-linearity, LCDV1, LCDV-C, and LCDV–Sa may represent three distinct species within the genus. Other LCDV isolates from yellow perch, rockfish, pearl gourami, glass fish and paradise fish have been reported and partial sequence data is available. Phylogenetic analysis based on MCP, DNA polymerase and myristylated membrane protein genes indicate that LCDV isolates display considerable sequence diversity. In view of the above, the number of species within the genus will likely be revised in the future.
Viral replication: A lack of cell lines suitable for in vitro replication has hindered analysis of LCDV biogenesis. Because few studies have been conducted, it has been assumed that LCDV replication is generally similar to FV3. Electron microscopy indicates that as with other iridovirids, virus assembly occurs in and around virogenic stroma within viral assembly sites.
The MCP is antigenic and protective antibodies are produced following exposure to this protein. There are other immunogenic viral proteins including one of 60 kDa for which a polyclonal antiserum provides a diagnostic reagent (Cano et al., 2006). In addition, monoclonal antibodies have been raised against several LCDV proteins and used in indirect immunofluorescence (IFA), Western blot, and enzyme-linked immunosorbent (ELISA) assays (Cheng et al., 2006).
LCDV1 and LCDV-C infect flounder and plaice, LCDV2 dab, and LCDV-Sa gilthead seabream. Furthermore, although a variety of viral isolates have been obtained from other infected fish species, it is unclear whether these isolates represent novel viral species, or simply strains/isolates with a broad host range. Infection targets fibroblasts and results in wart-like lesions comprising grossly hypertrophied cells occurring mostly in the skin and fins (Flugel 1985). The disease has been observed in over 100 teleost species although viral species other than LCDV may cause a similar clinical disease. The duration of infected cell growth and viral proliferation is highly variable (5 days to 9 months) and is likely temperature-dependent. Virions are released following degeneration of the lesions. Transmission is achieved by contact; external sites, including the gills, are the principal portals of entry. High host population densities and external trauma are believed to enhance transmission. Implantation and injection are also effective routes of transmission. The incidence of disease may be higher in the presence of certain fish ectoparasites. LCDV is not considered to be of major economic importance in fish since mortality is low. However, although infections are usually benign and self-limiting, there may be commercial concerns because the unsightly appearance of infected fish leads to market rejection. Moreover, mortalities may occur when infections involve the gills or when there is debilitation or secondary bacterial infection. LCDV is difficult to culture in vitro although limited growth has been reported in some fish cell lines.
Definitive criteria have not yet been established to delineate viral species. In the future, species may be distinguished from one another by molecular criteria, e.g., DNA sequence analysis and PCR. PCR primers targeted to regions within the MCP and ORF167L can be used to identify isolates.
Isolates are named after the associated disease and the chronological order in which the sample was isolated (e.g., LCDV1), the geographic location of the isolate (e.g., LCDV-C, China), or the host from which is was isolated (e.g., LCDV-Sa, Sparus auratus).
GenBank Acc. No.
lymphocystis disease virus – China
lymphocystis disease virus – Sparus auratus (LCDV-SA)
lymphocystitis disease virus-paradise fish (LCDV-PF)
lymphocystis disease virus – painted glassfish
lymphocystis disease virus – pearl gourami
lymphocystis disease virus - rockfish
These viruses likely represent new species within the genus or strains/isolates of previously identified lymphocystivirus species. The genomes of LCDV-C and LCDV-SA have been fully sequenced, whereas only the major capsid protein gene and two others have been sequenced from LCDV-PF and the other isolates.
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