Iridoviridae - v201911


Iridoviridae - v201911

V. Gregory Chinchar​, Paul Hick, Ikbal Agah Ince​, James K Jancovich, Rachel Marschang​, Qiwei Qin, Kuttichantran Subramaniam​, Thomas B Waltzek, Richard Whittington, Trevor Williams and Qi-Ya Zhang

Chapter contents

Posted May 2017, revised May 2018

Iridoviridae: The family

Member taxa

Supporting information

Citation

A summary of this ICTV Report chapter has been published as an ICTV Virus Taxonomy Profile article in the Journal of General Virology, and should be cited when referencing this online chapter as follows:

Chinchar, V.G., Hick, P., Ince, I.A., Jancovich, J.K., Marschang, R., Qin, Q., Subramaniam, K., Waltzek, T.B., Whittington, R., Williams, T., Zhang, Q., and ICTV Report Consortium. 2017, ICTV Virus Taxonomy Profile: IridoviridaeJournal of General Virology, 98, 890891.

Summary

The family Iridoviridae comprises large icosahedral, double-stranded DNA (dsDNA)-containing viruses. The family is divided into two subfamilies, Alphairidovirinae and Betairidovirinae. The former is comprised of three genera (Ranavirus, Megalocytivirus and Lymphocystivirus) whose members infect primarily ectothermic vertebrates such as bony fish, amphibians and reptiles, whereas the latter contains two genera (Iridovirus and Chloriridovirus) that infect mainly invertebrates such as insects and crustaceans. Viral replication involves both nuclear and cytoplasmic compartments; virion assembly takes place in the cytoplasm within morphologically distinct viral assembly sites. Mature, non-enveloped, but otherwise infectious, virions may remain within the cytoplasm from which they are released by cell lysis, or virions may acquire an envelope by budding from the plasma membrane. To avoid confusion between members of the genus Iridovirus and members of the family, members of the family will be referred to as iridovirids, rather than iridoviruses.

Table 1.Iridoviridae. Characteristics of the family Iridoviridae.

Characteristic

Description

Typical member

frog virus 3 (AY548484), species Frog virus 3, genus Ranavirus

Virion

Typically 150–200 nm (non-enveloped); the principal component of the capsid is the 48 kDa major capsid protein

Genome

Linear, double-stranded DNA, 103–220 kbp, encoding 92–211 putative proteins ; the genome is circularly permuted and terminally redundant

Replication

First stage DNA synthesis and early transcription take place in the nucleus; subsequently DNA concatemer formation and late transcription occur in the cytoplasm; virion morphogenesis takes place in cytoplasmic assembly sites

Translation

Directly from capped, non-polyadenylated mRNAs

Host Range

Subfamily Alphairidovirinae, members infect amphibians, fish, reptiles; subfamily Betairidovirinae, members infect mainly insects and crustaceans.

Taxonomy

Five genera divided between two subfamilies

Virion

Morphology

Virions consist, of a central DNA/protein core surrounded in turn by an internal limiting membrane, a viral capsid, and, in the case of those particles that bud from the plasma membrane, an outer viral envelope (Figure 1.Iridoviridae). SDS-PAGE analysis indicates the presence of approximately 30 virion-associated proteins, while proteomic analyses suggest higher numbers (Wong et al., 2011, Ince et al., 2015). Although some virion-associated proteins such as the major capsid protein, comprise structural elements of the particle, others serve catalytic or regulatory roles, e.g., the virion-associated transactivator of immediate-early transcription. Viral capsids display icosahedral symmetry (Figure 2A.Iridoviridae) and are usually 120–200 nm in diameter, but may be up to 350 nm (e.g. genus Lymphocystivirus). The virion core is electron-dense and consists of a DNA-protein filament enclosed within an icosahedral capsid (Figure 1.Iridoviridae).

Figure 1.Iridoviridae. Schematic diagram of a cross-section of an iridovirus particle, showing capsomers, the internal lipid bilayer containing transmembrane proteins and the filamentous nucleoprotein core (from (Darcy-Tripier et al., 1984) with permission).

Figure 2.Iridoviridae. A: Outer shell of invertebrate iridescent virus 2 (IIV2). Shown are trisymmetrons (orange) comprising the 20 icosahedral faces and pentrasymmetrons (red) located at the 12 vertices, and disymmetrons (blue) located at the edges of the icosahedral faces (Adapted from (Wrigley 1969) with permission). B: Cryo-transmission electron micrograph of IIV6 displaying a fringe of hair-like fibers surrounding the viral particle (figure provided by IA Ince and J van Lent).

Each virion is formed of 12 pentasymmetrons and 20 trisymmetrons arranged in an icosahedral, quasi-equivalent symmetry with a triangulation number T=147 (h=7, k=7) (Yan et al., 2009). Both types of structure predominantly comprise hexavalent capsomers, a total of 1,460 per virion, that are composed of the major capsid protein (MCP). Each hexavalent capsomer is formed by a non-covalent MCP trimer on the outer surface and a second MCP trimer linked by disulfide bonds on the inner surface. In addition, each pentasymmetron comprises 30 hexavalent (trimeric) capsomers and a single pentavalent capsomer at its center, at the vertex of each pentasymmetron, for a total of 12 in each virion.

Several proteins have been identified in the capsid shell and in association with the internal lipid membrane (Yan et al., 2009). These have been named zip monomers, zip dimers, finger proteins and anchor proteins. The zip dimers appear as two halves of a clasp connecting the trimer capsomers along the edges of adjacent trisymmetrons, whereas zip monomers appear to be involved in linking trisymmetron capsomers with those of neighboring pentasymmetrons. Three sets of nine inward-pointing finger proteins bind the capsomers along the edges of each trisymmetron. Finally, an anchor protein connects each pentasymmetron with the lipid membrane at a distance of two capsomers from the pentavalent vertex. Other transmembrane proteins are present, but only the anchor protein can be visualized in image reconstruction studies due to its invariant position with respect to the symmetry of the particle. Size estimates using the MCP as reference suggest molecular masses of 11.9, 19.7 and 32.4 kDa for the zip, finger and anchor proteins, respectively.

Among members of the Iridovirus, Chloriridovirus and Lymphocystivirus genera, the outer surface of the capsid is covered by flexible fibrils or fibers (Figure 2B.Iridoviridae). Conventional EM studies suggest that these fibrils are often rather short (ca. 2.5 nm in length) and may have terminal knobs, but in IIV6 a single fibril 2 nm wide and about 35 nm long extends outwards from the center of each trimeric capsomer . The role of the fibrils remains unknown. Fibers have not been reported among ranaviruses or megalocytiviruses.

Iridovirids may acquire an envelope by budding through the host cell membrane. The envelope increases the specific infectivity of virions, but is not required for infectivity as naked particles are also infectious.  

Physicochemical and physical properties

The Mol wt of virions is 1.05–2.75×109 with a sedimentation coefficient (S20,w) of 2020–4460S and a density of 1.26–1.60 g cm−3. Virions are stable in water at 4°C for extended periods. Iridovirids are inactivated by pH <3.0 and >11.0 and by exposure to UV-irradiation on the order of 103 μWs/cm2. Virions are inactivated within 30 min at >55°C. Some ranaviruses remain infectious after desiccation, e.g., Bohle iridovirus (BIV) survives desiccation at temperatures up to 42°C for up to 6 weeks, whereas others are sensitive to drying.

Nucleic acid

Virions contain a single linear double-stranded DNA molecule of 140–303 kbp, a value that includes both unique and terminally redundant sequences. However, when considering only the unique portion, genomes range in size from 103 to 220 kbp, depending upon the specific viral species (Table 2.Iridoviridae). DNA comprises 12–16% of the particle weight, and the G+C content ranges from about 27 to 55%. All viruses within the family possess genomes that are circularly permuted and terminally redundant. The DNA of vertebrate iridoviruses (subfamily Alphairidovirinae) is, with the exception of the grouper ranaviruses GIV and SGIV, highly methylated, whereas little to no methylation is found within the genomes of the invertebrate iridoviruses (subfamily Betairidovirinae). The complete genomic sequence is known for over 40 members of the family with representative sequence information available for every genus (Table 2.Iridoviridae). Although naked genomic DNA is not infectious, non-genetic reactivation of viral DNA can be achieved in the presence of viral structural proteins

Table 2.Iridoviridae. Iridovirus genome content.

Subfamily Alphairidovirinae

Genus

Species

Isolate

Genome (bp)

ORFs

%GC

Accession number

Lymphocystivirus

Lymphocystis disease virus 1

lymphocystis disease virus 1 (LCDV1)

102,653

108

29

L63545

 

 

 

 

 

 

 

Ranavirus

Frog virus 3

frog virus 3 (FV3)

105,903

97

55

AY548484

 

Bohle iridovirus

Bohle iridovirus (BIV)

103,531

100

55

KX185156

 

Ambystoma tigrinum virus

Ambystoma tigrinum virus (ATV)

106,332

92

54

AY150217

 

European catfish virus

European catfish virus (ECV)

125,549

136

54

KT989885

 

Epizootic haemapoietic necrosis virus

epizootic hemapoietic necrosis virus (EHNV)

127,011

100

54

FJ433873

 

Common midwife toad virus

common midwife toad virus (CMTV)

106,878

104

55

JQ231222

 

Santee-Cooper ranavirus

largemouth bass virus (LMBV)

NDa

ND

ND

DQ159940

 

Singapore grouper iridovirus

Singapore grouper iridovirus (SGIV)

140,131

139

49

AY521625

 

 

 

 

 

 

 

Megalocytivirus

Infectious spleen and kidney necrosis virus

infectious spleen and kidney necrosis virus (ISKNV)

111,362

117

55

AF371960

 

Subfamily Betairidovirinae

Genus

Species

Isolate

Genome

bp

ORFs

%GC

Accession number

Iridovirus

Invertebrate iridescent virus 6

invertebrate iridescent virus 6 (IIV6)

212,482

211

29

AF303741

 

Invertebrate iridescent virus 1

invertebrate iridescent virus 1 (IIV1)

NDb

ND

ND

M33542

 

 

 

 

 

 

 

Chloriridovirus

Invertebrate iridescent virus 3

invertebrate iridescent virus 3 (IIV3)

191,132

126

48

DQ643392

a ND: not determined. The genome sequences of largemouth bass virus, doctor fish virus and guppy virus 6 are unpublished, but the nucleotide sequences of their 26 core protein genes have been determined and aligned with those of other members of the family; all three isolates are placed in the species Santee-Cooper ranavirus. Accession numbers are for the the major capsid protein genes of these isolates.
b The sequence of the IIV1 genome has not been determined. The accession number is that of the major capsid protein.

Proteins

Nucleotide sequence analysis has identified more than 100 ORFs among various members of the family (Tables 2 and 3.Iridoviridae, Figure 3.Iridoviridae) of which 26 are common to all iridovirids (Eaton et al., 2007). As discussed below, viral proteins can be ordered into one of three, somewhat overlapping, categories: catalytic, structural, and virulence-related.

Figure 3.Iridoviridae. Genetic organization of a representative member of the family Iridoviridae, Ambystoma tigrinum virus (ATV), species Ambystoma tigrinum virus, genus Ranavirus. Arrows represent viral ORFs with their size, position and orientation shown. ORFs of known function are colored red and their putative proteins identified; ORFs with known homology to tiger frog virus (TFV) but of unknown function are shaded blue; and those of unknown function or with no homology to TFV are indicated in black.

Catalytic proteins comprise the majority of the 26 conserved proteins and include the virus-encoded DNA polymerase, the two largest subunits of the viral homolog of RNA polymerase II (vPOL-II), and the small subunit of ribonucleotide reductase (Table 3.Iridoviridae). In most cases their assigned function is putative and based on homology with other proteins in the database. However, in some cases, function has been confirmed experimentally, e.g., knock down of vPOL-IIα using an antisense morpholino oligonucleotide results in a marked reduction in late viral gene expression and supports its role as a viral transcriptase.

Iridovirid particles are complex assemblies of both structural and virion-associated proteins. Aside from structural elements such as the MCP and the aforementioned zip, finger, and anchor proteins, virions contain an additional 30 (or more) proteins ranging in mass from 5 to 250 kDa. The major capsid protein (MCP, 48–55 kDa) is highly conserved among all iridovirids and comprises 40% of the total virion protein mass. The amino acid (aa) sequence of the MCP has been used in virus identification and in phylogenetic analyses.

In addition to canonical structural proteins that contribute to the shape and integrity of the virion, there are a number of virion-associated proteins that play specific roles in viral replication. For example, virions encode a putative transcriptional transactivator that directs the expression of immediate-early viral genes. Furthermore, at least six DNA-associated polypeptides have been identified within the core of IIV6 including a major species of 12.5 kDa. Likewise, a number of virion-associated enzymatic activities have been detected, including a protein kinase, nucleotide phosphohydrolase, a ss/dsRNA-specific ribonuclease, pH 5 and pH 7.5 deoxyribonucleases, a protein phosphatase and a protein that triggers the shutdown of host macromolecular synthesis. In addition to these polypeptides, various other putative catalytic proteins have been identified by BLAST analysis some of which are encoded by all family members (Table 3.Iridoviridae; Figure 3.Iridoviridae).

Lastly several putative virulence or immune evasion proteins that enhance viral replication in restrictive environments (e.g., quiescent cells) or block host immune responses have been detected (Grayfer et al., 2015). Among the former are viral homologs of dUTPase, thymidine kinase, and ribonucleotide reductase that maintain deoxyribonucleotide pools during viral infection, whereas among the latter, vCARD, vIF-2α, vRNase III, and β-steroid dehydrogenase may function to block innate and acquired immunity (Grayfer et al., 2015). For example, vIF-2α, the viral homolog of eukaryotic translational initiation factor eIF-2α, blocks translational shut-off mediated by protein kinase R and maintains viral protein synthesis during infection (Rothenburg et al., 2011).

Table 3.Iridoviridae. Core genes of members of the family Iridoviridaea

ORFb

Putative function 

Categoryc

 

ORFb

Putative function

Categoryc

1R

Putative replication factor and/or DNA binding/packaging protein

C

 

57R

Serine/threonine protein kinase

C

2L

Myristylated membrane protein

S

 

60R

DNA polymerase family B exonuclease

C

8R

DNA-dependent, RNA polymerase II, α subunit

C

 

62L

DNA-dependent, RNA polymerase II, β subunit

C

9L

NTPase/helicase

C

 

67L

Ribonucleotide reductase, small subunit (RRα)

C,V

12L

Unknown function

UNK

 

80L

RNase III

C,V

15R

AAA-ATPase, similar to poxvirus A32, required for DNA packaging

C

 

81R

Transcription elongation factor TFIIS

C

19R

Serine/threonine protein kinase

C

 

84R

Proliferating cell nuclear antigen (PCNA)

C

21L

Helicase family protein

C

 

85R

Deoxynucleoside kinase

C

22R

D5 family NTPase involved in DNA replication

C

 

88R

Erv/Alr family of thiol oxidoreductases

C,V

27R

Putative tyrosine kinase/LPS modifying enzyme

C,V

 

90R

Major capsid protein (MCP)

S

37R

NIF-NLI interacting factor

V

 

91R

Immediate early protein ICP-46

 

UNK

41R

Vaccinia virus early transcription factor

C

 

94L

Uvr/REP helicase

C

53R

Myristylated membrane protein

S

 

95R

Putative RAD2-type nuclease

C

a In addition to the 26 iridovirid core genes indicated above, 27 ranavirus specific genes and 13 amphibian-like ranavirus genes have been identified (Eaton et al., 2007, Jancovich et al., 2010). Of the 27 ranavirus-specific genes 24 are of unknown function, whereas the three that are known encode a CARD-containing protein (64R), dUTPase (63R) and neurofilament triplet H1-like protein (32R). Likewise only two of the 13 amphibian ranavirus-like genes (26R, vIF-2α; 82R, immediate early 18 kDa protein) have putative homologs.
b ORF designations are based on their positions within the genome of frog virus 3 (AY548484).
c The letters reflect the known or putative function of the indicated proteins: C, catalytic; S, structural, V, virulence; UNK, unknown. In addition, several catalytic proteins are likely found within virions as virion-associated proteins.

Lipids

Non-enveloped particles contain 5–17% lipid, predominantly as phospholipid. Virions possess an internal lipid membrane that lies between the DNA core and the viral capsid, and, in budded virions, an outer viral envelope is acquired from the plasma membrane. The origin of the internal lipid membrane is unclear but, based on evidence from other nuclear cytoplasmic large DNA viruses (NCLDV) such as vaccinia virus, African swine fever virus, and Paramecium bursaria chlorella virus, it is likely derived from breakdown of the host endoplasmic reticulum (Romero-Brey and Bartenschlager 2016, Milrot et al., 2016). By analogy to other NCLDVs the internal membrane likely plays a key role in virion assembly by serving as a scaffold on which capsid protein deposition takes place.

Carbohydrates

Carbohydrate-containing proteins (glycoproteins) have been detected within lymphocystis disease virus and are likely present within other members of the family (Garcia-Rosado et al., 2004).

Genome organization and replication 

Iridovirid genomes consist of a unique component and a variable amount of terminal redundancy. The unique component ranges from 103 to 220 kbp, whereas the actual genome content is 5–50% larger for members of different species due to the presence of terminal redundancy. With the exception of LCDV1 (103 kbp), genomes for members of the Lymphocystivirus, Iridovirus and Chloriridovirus genera are larger (163–220 kbp) than those for members of the Megalocytivirus and Ranavirus genera (103–140 kbp). With the exception of SGIV, members of species within the Ranavirus genus tend to show marked sequence co-linearity. However, even within this genus, genome inversions and deletions have been noted. Putative open reading frames (ORFs) are found on both strands of the viral genome, but overlap of coding regions is rare (Figure 3.Iridoviridae). Moreover, gene density is high, intergenic regions are generally short, and genomes contain repetitive sequences. In contrast to eukaryotes, iridovirid genes lack introns and viral mRNAs lack poly[A] tails. However, like eukaryotes, biochemical and in silico evidence suggest the existence of viral microRNAs (miRNA) that modulate viral gene expression.

Iridovirids employ a novel replication strategy involving both nuclear and cytoplasmic stages that has been elucidated primarily through the study of FV3, the type species of the genus Ranavirus (Chinchar et al., 2009, Jancovich et al., 2015a, Williams et al., 2005). Although the precise mechanism of virion entry remains to be elucidated, multiple routes have been implicated including receptor-mediated endocytosis by enveloped particles, uncoating at the plasma membrane by naked virions, pinocytosis and caveola-dependent endocytosis (Wang et al., 2014). Following uncoating, viral DNA cores enter the nucleus where first stage DNA synthesis and the synthesis of immediate early (IE) and delayed early (DE) viral transcripts take place (Figure 4.Iridoviridae). In a poorly understood process, one or more virion-associated proteins acts as a transcriptional transactivator and re-directs host RNA polymerase II to synthesize IE viral mRNAs using the methylated viral genome as template. Gene products encoded by IE (and perhaps DE) viral transcripts include both regulatory and catalytic proteins. One of these gene products, the viral DNA polymerase, catalyzes the first stage of viral DNA synthesis in which the parental viral genome serves as the template, and progeny DNA is synthesized that is genome-length to at most twice genome length. Newly-synthesized viral DNA may serve as the template for additional rounds of DNA replication or early transcription, or viral DNA may be transported to the cytoplasm where the second stage of viral DNA synthesis occurs. There, viral DNA synthesis results in the formation of large, branched concatemers. Viral DNA methylation also occurs in the cytoplasm and, although its precise role is uncertain, it is thought to protect viral DNA from virus-mediated endonucleolytic attack. Synthesis of late (L) viral transcripts takes place in the cytoplasm and is catalyzed by virus-encoded homologs of RNA polymerase II (Sample et al., 2007). Similar to other large DNA viruses, full L gene expression requires prior DNA synthesis. Thus temperature-sensitive mutants that fail to synthesize viral DNA at the non-permissive temperature, and infected cells incubated in the presence of inhibitors of DNA synthesis, display markedly reduced levels of late viral transcripts and proteins. Virion formation takes place in the cytoplasm within morphologically distinct regions termed virus assembly sites (Figure 5.Iridoviridae). Assembly sites form in cells treated with an antisense morpholino oligonucleotide (asMO) targeted against vPOL-IIα indicating that assembly site formation does not require the synthesis of late viral gene products (Sample et al., 2007). Concatemeric viral DNA is thought to be packaged into virions via a “headful” mechanism that results in the generation of circularly-permuted and terminally-redundant genomes. Following assembly, virions accumulate in the cytoplasm within paracrystalline arrays or acquire an envelope by budding from the plasma membrane (Liu et al., 2016). In the case of most vertebrate iridoviruses, the majority of virions remain cell-associated (Figure 5.Iridoviridae).

Figure 4.Iridoviridae. Replication strategy of frog virus 3 (FV3). Replication begins in the nucleus with the synthesis of early viral transcripts and the synthesis of unit size, to twice unit size, DNA genomes that are subsequently transported to the cytoplasm where a second round of DNA replication results in the formation of large concatemers. Late messages are synthesized in the cytoplasm using a multi-subunit, virus-encoded transcriptase. Virion formation takes place in morphologically distinct assembly sites and viral particles are seen within assembly sites, paracrystalline arrays, and budding from the plasma membrane.

Figure 5.Iridoviridae. Transmission electron micrograph of a fathead minnow cell infected with FV3. Nucleus, N, showing signs of chromatin condensation (CC); a large electron-lucent assembly site (*) containing numerous immature, empty virions, few mature virions, and devoid of cellular organelles; a paracrystalline array of virus particles (large arrow); budding virions (small arrow); scale bar = 1 µm (figure provided by VG Chinchar and RC Sample).

Antigenicity 

Members of different genera within the family are serologically distinct from one another, whereas cross-reactivity among members of different species within a given genus may occur due to sequence conservation of the MCP and other viral proteins (Ariel et al., 2010). Three piscine ranaviruses (EHNV, ECV, and European sheatfish virus (ESV)) display serological cross-reactivity with each other and with FV3 (Hedrick et al., 1992).

Studies of FV3-infected Xenopus laevis indicate a marked antibody response following secondary infection and the generation of protective neutralizing antibodies (Grayfer et al., 2015). Furthermore, consistent with a protective antibody response, inactivated virus vaccines protect against disease mediated by RSIV. In addition, in the FV3/Xenopus laevis model, T cells have been implicated in protection against viral disease (Grayfer et al., 2015, Morales and Robert 2007). However, the precise FV3 proteins that trigger a T cell response are not known.

Biology

Iridovirids have been isolated only from ectothermic vertebrates and invertebrates, usually associated with damp or aquatic environments, including marine and freshwater habitats. Iridovirid species vary widely in their members’ natural host range and virulence.  

Invertebrate iridoviruses may be transmitted perorally, e.g. by cannibalism, as well as by endoparasitic wasps or parasitic nematodes. Infections with invertebrate iridoviruses fall into two categories: patent and covert. In the former, virus replication is extensive and infected animals display blue or green iridescence due to the presence of large numbers of virions within infected tissues. In the latter case, which is more common, lower levels of virus are present and iridescence is absent. However, despite the lower viral burden, covertly infected animals often experience reduced fitness (Williams et al., 2005).

Members of the genera Megalocytivirus and Lymphocystivirus infect only fish, whereas members of the genus Ranavirus infect fish, amphibians, and reptiles. Viruses may be transmitted experimentally by injection or bath immersion, and naturally by co-habitation and feeding, including cannibalism or scavenging of infected carcasses. Both megalocytiviruses and ranaviruses replicate within internal organs and, in the case of FV3, the kidney is a major target. In contrast, fish infected with lymphocystiviruses display wart-like growths on external surfaces (and sometimes internal organs) that are the result of greatly enlarged individual, virus-infected cells. Unlike infections with megalocytiviruses or ranaviruses that can produce mortality rates of nearly 100%, infections with lymphocystiviruses resolve spontaneously and mortality rates are generally low. 

Subfamily demarcation criteria

The two subfamilies within the family Iridoviridae are distinguished by their primary hosts. Members of the Alphairidovirinae infect mainly ectothermic vertebrates (bony fish, amphibians, and reptiles), whereas members of the Betairidovirinae infect mainly invertebrates (insects and crustaceans). Furthermore members of the latter subfamily tend to have larger genomes with a lower G+C content.

Genus demarcation criteria

Members of the five genera within the family are distinguished by nucleotide/amino acid sequence identity, host range, G+C content, phylogenetic relatedness, genome co-linearity, disease manifestations and antigenicity. Members of species within the same genus generally show greater than 50% sequence identity within a common set of core genes.

Derivation of names

Chloro: from the Greek chloros, meaning green

Cysti: from Greek kystis, indicating a bladder or sac

Irido: from Greek iris, iridos, the goddess whose sign was the rainbow, hence iridescent, from the appearance of patently-infected invertebrates and centrifuged pellets of virions

Lympho: from Latin lympha, meaning water

Megalocyti: from the Greek, meaning “enlarged cell”

Rana: from Latin rana, “frog,” the source of the first isolates

Alpha/Beta: Greek letters indicating the chronological order in which iridovirid pathogens of vertebrates and insects were identified

Phylogenetic relationships within the family

Phylogenetic analyses (Figure 6.Iridoviridae), based on individual genes, or a concatenated set of 26 genes common to all members of the family, support the division of the family into two subfamilies and five genera (Chinchar et al., 2011, Jancovich et al., 2015b). Viruses within a genus generally share greater than 50% identity at the nucleotide and amino acid levels. Moreover, viruses displaying greater than 90% sequence identity may belong to the same species or may be isolates/strains of the same species. For example, the ranaviruses FV3, ATV, and EHNV show >90% sequence identity, but differ in host range and genomic organization and thus are viewed as separate species rather than different isolates of the same species. Furthermore, the eight currently recognized species within the genus Ranavirus fall into three distinct phylogenetic clusters (Figure 6.Iridoviridae), while megalocytiviruses fall into two clusters and lymphocysitiviruses fall into two or three clusters. Several unclassified viruses (IIV9, IIV22, IIV22a, IIV25, IIV30, and AMIV) placed within the genus Iridovirus in the 9th ICTV Report, are more closely related to IIV3, a member of the genus Chloriridovirus.

As a consequence, the status of currently recognized viral species within these genera is being re-evaluated, taking into account criteria such as host range, gene order, the presence or absence of specific genes, nucleotide and amino acid sequence identity, and antigenicity.

Figure 6.Iridoviridae: Phylogenetic analysis of family Iridoviridae. Tips are labelled with sequence accession numbers and virus isolate names. Isolates with boldface indicate exemplar isolates for species. Genus and subfamily assignments are shown to the right.  The tree was constructed using maximum likelihood analysis in IQTREE and the concatenated amino acid (aa) sequences of 26 core genes (19,773 aa characters including gaps) from 45 completely sequenced iridovirus genomes. The tree was midpoint rooted and branch lengths are based on the number of inferred substitutions, as indicated by the scale bar. All branch points (i.e., nodes) separating genera are supported by bootstrap values greater than 99%. For other branch points all bootstrap values are >70% except for those displaying high levels of amino acid similarity, e.g., tiger frog virus vs. Bohle iridovirus/German gecko ranavirus, 66%; pike perch iridovirus vs. common midwife toad virus/2013/NL, 49%; turbot reddish body iridovirus vs. red seabream iridovirus, 57%; and lemon yellow croaker iridovirus vs. turbot reddish body iridovirus, 56% (figure provided by K Subramaniam and TB Waltzek). This phylogenetic tree and corresponding sequence alignment are available to download from the Resources page.

Similarity with other taxa

Iridovirid homologs of D5 ATPase, A32 ATPase, the A1L/VLTF2 transcription factor, MCP and viral DNA polymerase display amino acid sequence similarity with African swine fever virus and members of the families Ascoviridae, Phycodnaviridae, Mimiviridae and Poxviridae (Boyer et al., 2009). These relationships have prompted the suggestion that these viruses share a common origin and constitute members of a proposed new virus order, the Megavirales (Colson et al., 2013). Likewise, using a concatenated set of 9 genes common to iridovirids, ascoviruses and marseilleviruses, the close relationship between ascoviruses and invertebrate iridescent viruses has been confirmed, suggesting that ascoviruses emerged recently and share a common ancestor with IIV6 and IIV3 (Piegu et al., 2015). However, given the markedly different morphologies and replication strategies of ascoviruses and iridoviruses (Federici et al., 2009), additional analysis will be required to resolve the complicated phylogeny of members of these two distinct, yet related, families.

Related, unclassified viruses

Virus name

Accession number

Virus abbreviation

Genome (bp)

ORFs

%GC

Cherax quadricarinatus iridovirus

MF197913

CQIV

165,695

178

35

shrimp hemocyte iridescent virus

MF599468

SHIV

165,809

170

35

Daphnia iridescent virus 1

LS484712

DIV1

288,000

367

39

Virus names and abbreviations are not official ICTV designations.

Subfamily: Alphairidovirinae

Distinguishing features

Viruses within the subfamily infect primarily ectothermic vertebrates, i.e., bony fish (superclass Osteichthyes), amphibians and reptiles. In addition, members of the subfamily display the following characteristics: (1) they encode a DNA methyltransferase that methylates cystosine residues within CpG dinucleotides (with the exception of SGIV and GIV), (2) with the exception of some lymphocystiviruses, their genomes are generally smaller (103–140 kbp compared to ~200 kbp) with a higher G+C content (49–55% compared to 28–48%) than those of betairidoviruses.

Genus demarcation criteria

The three genera within the subfamily are distinguished by differences in sequence identity, phylogenetic relationships, host species, G+C content, and clinical manifestations of viral infection.

Member taxa


Genus: Lymphocystivirus

Distinguishing features

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. Lymphocystivirus-infected cells display a thick hyaline capsule, a central enlarged nucleus, and prominent basophilic DNA cytoplasmic inclusions.

Virion

Morphology

Particle size varies from 198 to 227 nm for lymphocystis disease virus 1 (LCDV1) and 200 nm for lymphocystis disease virus 2 (LCDV2). The icosahedral capsid may show a fringe of fibril-like external protrusions about 2.5 nm in length. The presence of capsid fibers distinguishes lymphocystiviruses from members of the other two genera of vertebrate iridoviruses.

Physicochemical and physical properties

Virions are heat labile. Infectivity is sensitive to treatment with ether or glycerol.

Nucleic acid

Within the genus, genomes vary from 98 kbp (LCDV2) to 209 kbp (lymphocystis disease virus – Sparus auratus, LCDV-Sa), the last is the largest known genome among 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 (22%) with 5-methylcytosine at 74% of CpG. The complete DNA sequence is known for LCDV1, lymphocystis disease virus - China (LCDV-C), and LCDV-Sa, 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 of LCDV1 is much smaller than that of LCDV-C and LCDV-Sa. Whether this reflects critical biological differences between LCDV1 and LCDV-C/LCDV-Sa, or whether it reflects a sequencing error, perhaps due to the presence of repeat regions, and remains to be determined.

Proteins

Little is known about the protein composition of lymphocystiviruses. The reported genomes 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.

Genome organization and replication

The LCDV1 genome (103 kbp) contains 108 largely non-overlapping putative 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. LCDV2, isolated from dabs, possesses a genome estimated, by analysis of restriction enzyme fragments, to be 98 kbp. It has not yet been sequenced.

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 sequences in public databases. Although LCDV1 and LCDV-C possess 103 genes in common, their gene order is markedly different. Furthermore, a large number of tandem and overlapping repeated sequences are observed in the LCDV-C genome.

The genome of 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 match those in LCDV-C, 10 best match LCDV1, two match ORFs within the scale drop disease virus (unclassified isolate, Megalocytivirus) genome and the remaining four best match either fish (3 ORFs) or spider (1 ORF) genes.

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 frog virus 3. Electron microscopy indicates that as with other iridovirids, virus assembly occurs in and around virogenic stroma within viral assembly sites.

Antigenicity

The major capsid protein (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 lymphocystivirus proteins and used in indirect immunofluorescence (IFA), Western blot, and enzyme-linked immunosorbent (ELISA) assays (Cheng et al., 2006).

Biology

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.

LCDV1 and LCDV-C infect flounder and plaice, LCDV2 infects dab, and LCDV-Sa infects gilthead seabream. Isolates have also been obtained from other infected fish species, but their taxonomic position is unclear . 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 members of viral species other than Lymphocystis disease virus 1 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 to be 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.

Species demarcation criteria 

Definitive criteria have not yet been established to delineate viral species. In the future, species may be distinguished from one another by DNA sequence analysis and PCR. PCR primers targeted to regions within the MCP and ORF167L can be used to identify isolates.  

Phylogenetic analysis based on MCP, DNA polymerase and myristylated membrane protein genes indicates that lymphocystovirus isolates display considerable sequence diversity. Overall the genome of LCDV-Sa shares 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 sequence differences among 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 lymphocystivirus isolates from yellow perch, rockfish, pearl gourami, glass fish and paradise fish have been reported and partial sequence data is available. In view of the above, the number of species within the genus is currently under review.

Member species

Species Virus name(s) Exemplar isolate Exemplar accession number Exemplar RefSeq number Available sequence Other isolates Other isolate accession numbers Virus abbreviation Isolate abbreviation
Lymphocystis disease virus 1 lymphocystis disease virus 1 L63545 NC_001824 Complete genome LCDV1
Lymphocystis disease virus 2 lymphocystis disease virus-China China AY380826 NC_005902 Complete genome LCDV-C
Lymphocystis disease virus 3 lymphocystis disease virus-Sparus aurata SA9 KX643370 NC_033423 Complete genome LCDV-Sa
Virus names, the choice of exemplar isolates, and virus abbreviations, are not official ICTV designations.

Derivation of names

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 it was isolated (e.g., LCDV-Sa, Sparus auratus (gilthead seabream)).

Related, unclassified viruses

Virus name

Accession numbera

Virus abbreviation

Genome (bp)

 ORFs

%GC

lymphocystis disease virus – China

 

AY380826

LCDV-C

186,250

178

27

lymphocystis disease virus – Sparus auratus

KX643370

LCDV-Sa

208,501

183

33

lymphocystitis disease virus-paradise fish

KJ408271

LCDV-PF

ND

ND

ND

lymphocystis disease virus – painted glassfish

AB299163

LCDV-PaGl

ND

ND

ND

lymphocystis disease virus – pearl gourami

AB299164

LCDV-PeGr

ND

ND

ND

lymphocystis disease virus - rockfish

AY849392

LCDV-RF

ND

ND

ND

lymphocystis disease virus 2

AF338235

LCDV2

~98,000

ND

ND

Virus names and abbreviations are not official ICTV designations.
ND: not determined.
a Full genome sequences have been determined for LCDV-C and LCDV-Sa. For the other isolates, the major capsid protein gene sequence (LCDV-PF, -PaGl, -PeGr, and -RF) or a TNFαR-like protein (LCDV2) gene sequence have been determined.

Genus: Megalocytivirus

Distinguishing features

Megalocytiviruses infect multiple species of freshwater and marine fish. Although they are morphologically similar to ranaviruses, the unique component of their genomes is slightly larger (111–112 kbp) than most ranaviruses, except for Singapore grouper iridovirus/ grouper iridovirus and epizootic haematopoietic necrosis virus/ European sheatfish virus, but smaller than for members of the genera Iridovirus and Chloriridovirus and two of the three sequenced lymphocystiviruses. Megalocytiviruses are distinguished from ranaviruses and lymphocystiviruses by the presence of inclusion body-bearing cells and sequence analysis of key viral genes, e.g., ATPase and MCP, for which PCR primers have been developed. Most megalocytiviruses show >94% sequence identity within these genes, whereas sequence identity with ranaviruses and lymphocystiviruses is <50%. Infections in vivo lead to systemic, often life-threatening disease. Infections in vivo are characterized by the appearance of “inclusion body-bearing” cells. Inclusion body-bearing cells are hypertrophied cells containing large foamy or granular basophilic inclusions that distend the cytoplasm and displace the nucleus; they are pathognomonic for infection with megalocytiviruses.

Virion

Morphology

Virions possess icosahedral symmetry and are 140–200 nm in diameter. Virions are inactivated by heat (56°C for 30 min), sodium hypochlorite, UV irradiation, chloroform ether, and by exposure to pH3 and pH11.

Physicochemical and physical properties

Physical properties are likely to be similar to those of other members of the family (see family description)

Nucleic acid

The complete genomes of eight megalocytiviruses, infectious spleen and kidney necrosis virus (ISKNV), rock bream iridovirus, red seabream iridovirus (RSIV), orange spotted grouper iridovirus (OSGIV), turbot reddish body iridovirus (TRBIV), large yellow croaker iridiovirus, giant seaperch iridovirus, and scale drop disease virus (SDDV), have been sequenced. Megalocytivirus particles contain a single, linear dsDNA molecule of 110,104 to 112,636 bp with a G+C content of 53–55%. As with other members of the family, genomic DNA is circularly permuted, terminally redundant and highly methylated.

Proteins

The protein composition of megalocytiviruses has not been extensively studied. Inspection of viral genomes indicates the presence of between 93 and 135 putative genes.

Genome organization and replication

Replication of megalocytiviruses is assumed to be similar to that of frog virus 3. However, given that there are a number of putative ORFs that are genus-specific, it is also likely that megalocytivirus replication differs in some aspects. 

Antigenicity

In immunofluorescent antibody assays, a monoclonal antibody targeted to red seabream iridovirus detects ISKNV, but does not recognize fish ranaviruses. Cross-reactivity among megalocytiviruses is likely to reflect high levels of amino acid identity among viral proteins. Vaccines using inactivated virus or recombinant proteins have been developed, and the former has been licensed for commercial use.

Biology

Iridoviruses infecting red seabream, mandarin fish and over 30 other species of marine and freshwater fish have been known since the late 1980s. Isolates from red seabream (RSIV) and mandarin fish (ISKNV) have been studied extensively (Kurita and Nakajima 2012). In vivo, viral infection is characterized by the formation of inclusion body-bearing cells (IBC). IBCs frequently appear in hematopoietic tissues, i.e., spleen and kidney, gills, the digestive tract, and other tissues. Necrotized splenocytes are also observed. Transmission has been demonstrated by feeding, parenteral injection and environmental exposure. Megalocytiviruses naturally infect and cause significant mortality in freshwater and marine fish in aquaculture facilities in China, Japan and South East Asia. Infections have recently been identified in Australia and North America. A partial list of susceptible fish species includes mandarin fish (Siniperca chuatsi), red seabream (Pagrus major), grouper (Epinephelus spp.), yellowtail (Seriola quinqueradiata), striped beakperch (Oplegnathus fasciatus), red drum (Sciaenops ocellata) and African lampeye (Aplocheilichthys normani). The virus grows in several cultured piscine cell lines and causes a characteristic enlargement of infected cells. Outbreaks of disease caused by ISKNV occur only in fish cultured at temperatures >20°C. A vaccine targeted to RSIV has been developed suggesting that infection/immunization is capable of eliciting protective antibodies. 

Species demarcation criteria

Based on sequence analysis and serological studies, all megalocytiviruses isolated to date appear to be strains of the same or a small number of closely-related species. Phylogenetic analysis indicates the presence of two clusters, one composed of RSIV, ISKNV, TRBIV, and other highly similar viruses, and a second , more distant, cluster comprised of a single isolate, SDDV (Figure 6.Iridoviridae). Whether members of the larger cluster represent distinct species, or strains of a single species, remains to be resolved. In general ISKNV-like viruses have been isolated from freshwater fish, whereas RSIV-like viruses infect marine fish.

Member species

Species Virus name(s) Exemplar isolate Exemplar accession number Exemplar RefSeq number Available sequence Other isolates Other isolate accession numbers Virus abbreviation Isolate abbreviation
Infectious spleen and kidney necrosis virus infectious spleen and kidney necrosis virus AF371960 NC_003494 Complete genome ISKNV
Scale drop disease virus scale drop disease virus C4575 KR139659 NC_027778 Partial genome SDDV
Virus names, the choice of exemplar isolates, and virus abbreviations, are not official ICTV designations.

Derivation of names

Megalocytiviruses have been named after the disease they cause (e.g., Infectious spleen and kidney necrosis virus) or the host species (red seabream iridovirus) they infect.

Related, unclassified viruses

This table only includes isolates whose genome has been fully sequenced.

Virus name

Accession number

Virus abbreviation

Genome (bp)

ORFs

%GC

rock bream iridovirus

AY532606

RBIV

112,080

116

53

red seabream iridovirus

BD143114

RSIV

112,414

93

53

orange spotted grouper iridovirus

AY894343

OSGIV

112,636

116

54

turbot reddish body iridovirus

GQ273492

TRBIV

110,104

115

55

large yellow croaker iridiovirus

AY779031

LYCIV

111,760

119

ND

giant seaperch iridovirus

KT804738

GSIV-K1

112,565

135

ND

scale drop disease virus

KR139659

SDDV

124,244

129

37

Virus names and abbreviations are not official ICTV designations.
ND: not determined.

Genus: Ranavirus

Distinguishing features

Ranaviruses infect one or more species within the classes Reptilia, Amphibia and Osteichthyes and cause systemic infections. Depending upon the virus and the age and species of the host, infected animals display a variety of clinical signs such as, internal organ hemorrhage, skin sloughing and external petechial hemorrhages. Among currently identified ranaviruses, sequence identity within the major capsid protein is approximately 70% or higher.

Virion 

Non-enveloped virus particles display a diameter of approximately 150 nm in ultrathin section, whereas enveloped virions measure 160–200 nm in diameter. The capsid has a skewed symmetry with T=133 or 147. The internal lipid bilayer likely contains transmembrane proteins. The nucleoprotein core consists of a long coiled filament 10 nm wide. 

Physicochemical and physical properties

Buoyant density is 1.28 g cm−3 for enveloped particles and 1.32 g cm−3 for non-enveloped particles. Infectivity is rapidly lost at pH 2.0–3.0 and at temperatures above 50°C. Particles are inactivated by treatment with ether, chloroform, sodium deoxychlorate and phospholipase A.

Nucleic acid

The genome is circularly permuted and approximately 30% terminally redundant with a unit size of 104–140 kbp and a G+C content of 49–55% (Table 1.Iridoviridae). With the exception of Singapore grouper iridovirus (SGIV), ranaviruses encode a cytosine DNA methyltransferase which methylates cytosines within the dinucleotide sequence CpG. Although there is one report to the contrary, DNA methylation is likely to occur in the cytoplasm and may protect viral DNA from virus-encoded endonucleolytic attack or prevent recognition by a Toll-like receptor 12-like protein.

Proteins

Ranavirus genomes contain 26 genes (i.e., open reading frames) that are shared with other members of the family. In addition, there are 27 genes that are found only among members of this genus. Most of the 26 core Iridoviridae genes show relatedness to previously characterized gene products (e.g., DNA polymerase, RNA polymerase II, etc.), whereas the 27 ranavirus-specific genes do not show identity with putative genes outside the genus Ranavirus suggesting that they may have specific roles in host-virus interactions. Ranavirus gene function has been explored through a variety of techniques including ectopic expression of viral proteins, the analysis of conditionally-lethal and knock out mutants, and the knock down of gene expression using either RNA silencing (RNAi) or antisense morpholino oligonucleotides (Jancovich et al., 2015b).

Genome organization and replication

The replication cycle of frog virus 3 (FV3) serves as the model for the family (Figure 4.Iridoviridae). The complete genomes of 25 ranaviruses (Table 1.Iridoviridae) have been sequenced and show marked genetic conservation. Based on whole genome dot plot comparisons there are four genomic phenotypes among them (FV3/tiger frog virus / soft-shelled turtle virus -like, Ambystoma tigrinum virus (ATV)/ epizootic haematopoietic necrosis virus (EHNV)-like, SGIV/ grouper iridovirus -like, and common midwife toad virus (CMTV)-like). FV3-, ATV-, and CMTV-like viruses display extensive regions of co-linearity, albeit with evidence of sequence inversions and deletions. In contrast, when compared to the other three, SGIV-like viruses only contain short regions of co-linearity and display extensive re-arrangement of the viral genome. However, despite the marked reshuffling of the genome, SGIV contains 53 ORFs in common with other ranaviruses. The apparent ability of ranaviruses to express conserved, functional gene products despite marked variations in co-linearity suggests that gene expression is not linked to gene order and is consistent with the previously observed high level of genetic recombination.

Antigenicity

Ranaviruses such as FV3 are serologically and genetically distinct from members of other genera. However, several piscine, reptilian and amphibian ranavirus isolates show serological cross-reactivity with FV3 (Hedrick et al., 1992). Serological cross-reactivity likely reflects marked amino acid sequence conservation (i.e., >90% identity) within the major capsid protein and other viral proteins.

Biology

Viral transmission occurs by feeding (scavenging or cannibalism), parenteral injection, direct contact, or environmental exposure. Ranaviruses are generally promiscuous pathogens and infect multiple species within a taxonomic class as well as members of different classes (Duffus et al., 2015). In vitro, ranaviruses replicate in a wide variety of cultured fish, amphibian, reptilian, avian and mammalian cells at temperatures up to 32°C. Infection causes cytopathic effects culminating in cell death, likely by apoptosis, and the marked inhibition of host DNA, RNA and protein synthesis. In contrast to their marked pathogenicity in vitro, the effect of ranavirus infections in vivo depends on the viral species and the identity, age, and health of the host animal. For example, the largemouth bass virus (LMBV) isolate of the species Santee-Cooper ranavirus shows evidence of widespread infection in the wild, but is only rarely linked to serious disease. Likewise, FV3 infection leads to death in tadpoles and stressed adults, but often causes only non-apparent subclinical infections in healthy adult frogs and resolves within two weeks. It is likely that environmental stress leading to immune suppression increases the pathogenicity of ranavirus infections. As with infections in vitro, ranavirus infections in vivo are often not limited to a single host species or taxonomic class of animal. For example, EHNV has been reported to infect at least 13 species of fish, and Bohle iridovirus (BIV), a highly virulent pathogen of the burrowing frog Lymnodynastes ornatus, can be experimentally transmitted to fish and reptiles. Therefore, isolation of a ranavirus from a new host species does not necessarily identify a new viral species as the same virus may infect many different hosts. Furthermore, the pathological consequences of ranavirus infections vary markedly. In the most severe cases, ranaviruses such as FV3, ATV, European catfish virus (ECV) and EHNV are associated with life-threatening systemic disease and show marked hemorrhagic involvement of internal organs such as the liver, spleen, kidney and gut (Miller et al., 2015). Although there is a tendency for younger animals to experience more severe disease than older ones, the clinical outcome of infection will vary with the specific virus and host, and with associated environmental stresses.

Species demarcation criteria

Ranavirus species are distinguished by multiple criteria including their members’ amino acid and nucleotide sequence identity, phylogeny, principal host species, genome size, genetic co-linearity, and gene content. Many isolates within the genus show >90% sequence identity within the major capsid protein and other conserved proteins. In view of this high level of sequence identity, a re-evaluation of the number of ranavirus species is currently underway.

Member species

Species Virus name(s) Exemplar isolate Exemplar accession number Exemplar RefSeq number Available sequence Other isolates Other isolate accession numbers Virus abbreviation Isolate abbreviation
Ambystoma tigrinum virus Ambystoma tigrinum virus AY150217 NC_005832 Complete genome ATV
Common midwife toad virus common midwife toad virus Pelophylax kl. esculentus/2013/NL KP056312 NC_039034 Complete genome CMTV
Epizootic haematopoietic necrosis virus epizootic haematopoietic necrosis virus Australia FJ433873 NC_028461 Complete genome EHNV
Frog virus 3 frog virus 3 AY548484 NC_005946 Complete genome FV3
Santee-Cooper ranavirus largemouth bass virus BG/TH/CU3 KU507317 NC_038508 Partial genome SCRV
Singapore grouper iridovirus Singapore grouper iridovirus AY521625 NC_006549 Complete genome SGIV
Virus names, the choice of exemplar isolates, and virus abbreviations, are not official ICTV designations.

Derivation of names

Ranavirus species are designated by one of three, albeit imperfect, naming methods: the host species from which the virus was first isolated (Ambystoma tigrinum virus, Common midwife toad virus, European catfish virus, Frog virus 3, and Singapore grouper iridovirus), the typical clinical manifestation of infection (Epizootic hematapoietic necrosis virus), or the geographic site of the first isolate (Bohle iridovirus, Santee-Cooper ranavirus).

Related, unclassified viruses

Only isolates whose genomes has been completely sequenced are included in this table

Virus name

Accession number

Virus abbreviation

Genome (bp)

ORFs

%GC

tiger frog virus

AF389451

TFV

105,057

105

55

Rana grylio virus

JQ654586

RGV

105,791

106

55

soft-shelled turtle virus

EU627010

STIV

105,890

103

55

German gecko ranavirus

KP266742

GGRV

103,681

73

55

spotted salamander – Maine

KJ175144

SSME

105,070

95

55

Testudo hermanni ranavirus

KP266741

CH8/96

105,811

75

55

pike-perch iridovirus

KX574341

PPIV

108,041

109

57

tortoise ranavirus 1)

KP266743

ToRV1

103,876

76

55

Andrias davidianus ranavirus

KC865735

ADRV

106,734

101

55

ranavirus maximus

KX574343

RMax

115,510

100

55

cod iridovirus

KX574342

CoIV

114,865

98

57

short-finned eel virus

KX353311

SERV

126,965

111

56

European sheatfish virus

JQ724856

ESV

127,732

136

54

grouper iridovirus

AY666015

GIV

139,793

139

49

Chinese giant salamander iridovirus– HN1104

KF512820

CGSIV

105,375

111

ND

Virus names and abbreviations are not official ICTV designations.
ND: not determined.

Subfamily: Betairidovirinae

Distinguishing features

Members of the subfamily Betairidovirinae have larger virions than vertebrate iridoviruses and often display fiber-like extensions to the capsid. They also generally have larger genomes that have a lower G+C content, lack the extensive cytosine methylation seen among vertebrate iridoviruses, and mainly infect invertebrate hosts. Although they infect a wide range of agricultural pests and medically-important insects such as mosquitoes, their study has, by and large, been neglected and important information regarding host range, number of viral species, and replication strategy is incomplete (Williams and Ward 2010, Williams et al., 2016).

Genus demarcation criteria

Historically members of the two genera were distinguished by virion size and the iridescent color of infected insects and purified virus stocks. Given increasing numbers of fully sequenced viral genomes within this subfamily, membership within, and composition of, the two genera will likely require revision as phylogenetic analysis (Figure 6.Iridoviridae) suggests alternative interpretations.

Member taxa


Genus: Chloriridovirus

Distinguishing features

Historically, the larger virion size (180 nm compared to 120–130 nm) and the yellow-green iridescence of patently-infected larvae and purified viral pellets were used to distinguish chloriridoviruses from iridoviruses. Chloriridoviruses were originally thought to only infect mosquito species, however recent phylogenetic studies suggest they may have a broader host range.

Virion

Morphology

Particle diameter is up to 180 nm in ultrathin section. The trimers and pentamers of invertebrate iridescent virus 3 (IIV3) are larger than the corresponding structures of members of the genus Iridovirus, with probably 14 capsomers to each edge of the trimer. Particle size has historically been used to define viruses that are members of this genus, but the validity of that characteristic is uncertain. A fringe of hair-like fibrils surrounds virus particles (Figure 2B.Iridoviridae).

Physicochemical and physical properties

IIV3 has a Mol Wt of approximately 2.49-2.75 ×109, a buoyant density of approximately 1.354 g cm−3 in CsCl, and a sedimentation coefficient of 4440–4460S.

Nucleic acid

The genome of IIV3 is 191,132 bp with a G+C content of 48%. Of the 126 predicted genes, 68 are common between invertebrate iridescent virus 6 (IIV6, genus Iridovirus) and IIV3. Thirty-three IIV3 genes lack homologs in other iridovirids. There is little conservation of gene order among IIV3, IIV6, and invertebrate iridescent virus 9 (IIV9), e.g., between IIV3 and IIV9 only five clusters of three or more genes were detected (Wong et al., 2011).

Proteins

Proteomic analysis of IIV9, an unclassified virus in the genus, suggests that up to 64 viral proteins are present within the virion. Putative genes found in IIV3 and IIV6 but not present in vertebrate iridovirids, include a DNA topoisomerase II, an NAD-dependent DNA ligase, SF1 helicase, IAP and a BRO protein. The genome of the type species, IIV3, is 191 kbp and encodes a minimum of 126 ORFs. Other unclassified viruses in the genus have 148–191 ORFs.

Genome organization and replication

Only very limited colinearity has been observed between IIV3 and the genome of any other IIVs sequenced to date. The genes of IIV3, like those of other members of the family, do not appear to be grouped by temporal class. Moreover, they lack introns, are closely-spaced, and are not present on overlapping strands of the viral genome. Because suitable in vitro replication systems are lacking, little is known about the viral replication strategy. However, as with other members of the family, overall replication strategy is thought to be similar to that of frog virus 3.

Antigenicity 

IIV3 is serologically distinct from members of other genera.

Biology

Chloriridovirus-like infections were reported from Diptera with aquatic larval stages, mainly mosquitoes. There is evidence for transovarial transmission in mosquitoes infected by IIV3. Horizontal transmission is achieved by cannibalism or predation of infected mosquitoes. Patently infected larvae and purified pellets of virus display yellow-green iridescence although orange and red infections are known. IIV3 appears to have a narrow host range.

Species demarcation criteria

Members of the genus show 50% or greater sequence identity within the major capsid protein gene. Criteria to distinguish species within the genus are under development. Isolates displaying 90% or greater nucleotide identity within the major capsid protein gene, or within a set of core genes, would likely be considered as members of the same viral species.

Member species

Species Virus name(s) Exemplar isolate Exemplar accession number Exemplar RefSeq number Available sequence Other isolates Other isolate accession numbers Virus abbreviation Isolate abbreviation
Anopheles minimus iridovirus Anopheles minimus iridovirus KF938901 NC_0123848 Complete genome AMIV
Invertebrate iridescent virus 3 invertebrate iridescent virus 3; mosquito iridescent virus Florida DQ643392 NC_008187 Complete genome IIV3; MIV
Invertebrate iridescent virus 9 Invertebrate iridescent virus 9 GQ918152 NC_015780 Complete genome IIV9
Invertebrate iridescent virus 22 Invertebrate iridescent virus 22 HF920633 NC_021901 Complete genome IIV22
Invertebrate iridescent virus 25 Invertebrate iridescent virus 25 HF960235 Complete genome IIV25
Virus names, the choice of exemplar isolates, and virus abbreviations, are not official ICTV designations.

Derivation of names

Invertebrate iridescent viruses (i.e., IIVs) were designated in the order in which they were identified. However, some were designated based on the host species from which they were isolated, e.g., Anopheles minimus iridovirus.

Related, unclassified viruses

Virus name

Accession number

Virus abbreviation

Genome (bp)

ORFs

%GC

invertebrate iridescent virus 9

GQ918152

IIV9

206,791

191

31

invertebrate iridescent virus 22

HF920633

IIV22

197,693

167

29

invertebrate iridescent virus 22A

HF920634

IIV22A

196,455

174

28

invertebrate iridescent virus 25

HF920635

IIV25

204,815

177

30

invertebrate iridescent virus 30

HF920636

IIV30

198,533

177

28

Anopheles minimus iridiovirus

KF938901

AMIV

163,023

148

ND

Virus names and abbreviations are not official ICTV designations.
ND: not determined.

These isolates are regarded as unclassified viruses most closely related to viruses in the genus Chloriridovirus. This conclusion is based on phylogenetic analyses that indicate that they are more closely-related to IIV3 than to IIV6 (Figure 6.Iridoviridae).


Genus: Iridovirus

Distinguishing features

In the past, iridoviruses were distinguished from chloriridoviruses by the color of the iridescence displayed by infected insects or concentrated virus stocks and by virion size. Recent phylogenetic analysis of 10 members of these genera suggests a revision is needed and that phylogenetic placement, rather than color or virion size, is the most appropriate metric to differentiate members of these two genera (Figure 6.Iridoviridae).

Virion

Morphology

Virions are icosahedral particles that may or may not be enveloped. Virions display a fringe of proteins surrounding the particle. Particle diameter is 120–130 nm in ultrathin section. Invertebrate iridescent virus 1 (IIV1) and invertebrate iridescent virus 2 (IIV2) are assumed to contain approximately 1,472 capsomers arranged as 20 trisymmetrons and 12 pentasymmetrons. A detailed description of virion morphology is presented in the Iridoviridae family section using invertebrate iridescent virus 6 (IIV6) as the model. 

Physicochemical and physical properties

Virions have a Mol Wt of approximately 1.28×109, a buoyant density of 1.30–1.33 g cm−3, and a sedimentation coefficient of 2,020–2,250S. IIV6 is sensitive to chloroform, SDS, sodium deoxycholate, ethanol, pH 3 and pH 11, but is not sensitive to trypsin, lipase, phospholipase A2 or EDTA. Sensitivity to ether and chloroform depends on the assay system employed.           

Nucleic acid

The 212 kbp genome of IIV6 contains 215 putative ORFs. Comparison of the IIV6 (genus Iridovirus) and invertebrate iridescent virus 3 (IIV3, genus Chloriridovirus) genomes shows no co-linearity.

Proteins

Although 215 ORFs have been identified in IIV6, it is unclear whether the large number of putative proteins is due to a more complex virion, or an increase in non-structural proteins that impact virulence, host evasion, and viral replicative events. SDS-PAGE has identified more than 30 virion-associated polypeptides ranging in size from 11–200 kDa whereas proteomic analysis suggests up to twice as many (Wong et al., 2011, Ince et al., 2010). The virion core contains a major component of 12.5 kDa and at least five additional proteins.

Genome organization and replication

Although IIV6 and IIV3 contain 68 ORFs in common, co-linearity is not seen indicating that, as with other iridovirids, gene order is plastic and genes within the same temporal class (i.e., immediate early, delayed early, and late) are not clustered. 

Antigenicity 

Early work indicated that IIV6 was serologically unrelated to any other small iridescent virus, but other isolates were related to various extents (see below). Cross-reactivity is likely to reflect the degree of sequence identity within the major capsid protein and other structural proteins. 

Biology 

Iridoviruses have been isolated from a wide range of arthropods, particularly insects in aquatic or damp habitats. For example IIV6 (also designated Chilo iridescent virus after the host from which it was first isolated, Chilo suppressalis, the rice stem borer) infects over 100 insect species. Patently infected animals and purified viral pellets display violet, blue or turquoise iridescence. Covert, non-lethal infections may be common in certain hosts. No evidence exists for transovarial transmission and where horizontal transmission has been demonstrated, it is usually by cannibalism or predation of infected invertebrate hosts. Following experimental infection, many members of the genus can replicate in a large number of insects. In nature, the host range appears to vary but there is evidence, for some viruses, of natural transmission across insect orders and even phyla. Invertebrate iridescent viruses have a global distribution. Interestingly, reptiles and amphibians fed iridovirus-infected insects appear to become infected (Papp et al., 2014)

Species demarcation criteria

The major capsid protein of IIV1 shows 66.4% amino acid (aa) sequence identity to that of IIV6 and approximately 50% or lower aa sequence identity to iridovirids in other genera. Less than 1% DNA–DNA hybridization was detected by the dot-blot method between IIV1 and IIV6 genomic DNA (stringency: 26% mismatch). Restriction endonuclease profiles (HindII, EcoRI, SalI) showed a coefficient of similarity of <66% between IIV1 and IIV6. Moreover, these species did not share common antigens when tested by tube precipitation, infectivity neutralization, reversed single radial immunodiffusion or enzyme-linked immunosorbent assay. Given the current ease of sequence determination, future demarcation of viral species will likely rely more on genomic sequence analysis, host range, clinical features, etc., and less on restriction endonuclease profiles, hybridization data, and immunological cross-reactivity.

Member species

Species Virus name(s) Exemplar isolate Exemplar accession number Exemplar RefSeq number Available sequence Other isolates Other isolate accession numbers Virus abbreviation Isolate abbreviation
Invertebrate iridescent virus 6 invertebrate iridescent virus 6; Chilo iridescent virus AF303741 NC_003038 Complete genome IIV6; CIV
Invertebrate iridescent virus 31 Invertebrate iridescent virus 31 HF920637 NC_024451 Complete genome IIV31
Virus names, the choice of exemplar isolates, and virus abbreviations, are not official ICTV designations.

Derivation of names

Invertebrate iridescent viruses (i.e., IIVs) were designated in the order in which they were identified. They were also given common names based on the host from which they were isolated, i.e., IIV6, Chilo iridescent virus; IIV1, Tipula iridescent virus. 

Related, unclassified viruses

For isolates apart from IIV31 (Armadillidium vulgare iridescent virus) only the major capsid protein sequence has been determined.

Virus name

Accession number

Virus abbreviation

Genome (bp)

ORFs

%GC

Anticarsia gemmatalis iridescent virus

AF042343

AGIV

ND

ND

ND

invertebrate iridescent virus 2

AF042335

IIV2

ND

ND

ND

invertebrate iridescent virus 16

AF025775

IIV16

ND

ND

ND

invertebrate iridescent virus 23

AF042342

IIV23

ND

ND

ND

invertebrate iridescent virus 24

AF042340

IIV24

ND

ND

ND

invertebrate iridescent virus 29

AF042339

IIV29

ND

ND

ND

invertebrate iridescent virus 31

HF920637

IIV31

220,222

203

35

Gryllus bimaculatus iridovirus

AF247641

GbIV

ND

ND

ND

Virus names and abbreviations are not official ICTV designations.
ND: not determined.

Authors: Iridoviridae

V Gregory Chinchar*
Iridoviridae Study Group Chair
Department of Microbiology
University of Mississippi Medical Center
Jackson
MS, 39216
USA
Tel: +1 601-984-1743
E-mail: vchinchar@umc.edu

Paul Hick
Sidney School of Veterinary Science
Faculty of Science
University of Sydney
Camden
NSW 2570
Australia
Tel: +61 2935 11608
E-mail: paul.hick@sydney.edu.au

Ikbal Agah Ince
Department of Medical Microbiology
School of Medicine
Acibadem University
34752 Atasehir
Istanbul
Turkey
Tel: +90 216 500 4124
E-mail: Ikbal.agah.ince@gmail.com

James Jancovich
Department of Biological Sciences
California State University
San Marcos
CA 92096
USA
Tel: +1 760-750-8525
E-mail: jjancovich@csusm.edu

Rachel Marschang
Laboklin GmbH & Co. KG
Steubenstrasse 4
97688 Bad Kissingen
Germany
Tel: +49 0711 1205740
E-mail: rachel.marschang@googlemail.com

Qiwei Qin
Key Laboratory of Tropical Marine Bio-Resources and Ecology
South China Sea Institute of Oceanology
Chinese Academy of Sciences
Guangzhou
China
E-mail: qinqw@scsio.ac.cn

Kuttichantran Subramaniam
Department of Infectious Diseases and Pathology
College of Veterinary Medicine
University of Florida
Gainesville
FL, 32611
USA
Tel: +1 352-273-5409
E-mail: ksubramaniam@ufl.edu

Thomas Waltzek
Department of Infectious Diseases and Pathology
College of Veterinary Medicine
University of Florida
Gainesville
FL, 32611
USA
Tel: +1 352-273-5303
E-mail: tbwaltzek@ufl.edu

Richard Whittington
Sydney School of Veterinary Science and School of Life and Environmental Science
Faculty of Science,
University of Sydney
Camden
NSW 2570
Australia
Phone: +61 9351 1619
E-mail: Richard.whittington@sydney.edu.au

Trevor Williams
Instituto de Ecologia AC
Xalapa
Veracruz 91070
Mexico
Tel: +52 228 842 1800
E-mail: trevor.inecol@gmail.com

QiYa Zhang
State Key Laboratory of Freshwater Ecology and Biotechnology
Institute of Hydrobiology
Chinese Academy of Sciences
Wuhan
Hubei
China
E-mail: lgui@zhou.edu.cn

* to whom correspondence should be addressed

The chapter in the Ninth ICTV Report, which served as the template for this chapter, was contributed by Jancovich, J.K., Chinchar, V.G., Hyatt, A., Miyazaki, T., Williams, T. and Zhang, Q.Y.


Resources: Iridoviridae

Global Ranavirus Consortium:

http://www.ranavirus.org

Sequence alignments and tree files:

Figure 6.Iridoviridae

Tree file (newick format)

Alignment file (FASTA format)


Further reading: Iridoviridae

Chinchar, V. G. (2002). Ranaviruses (family Iridoviridae): emerging cold-blooded killers. Arch Virol 147, 447-470. [PubMed]

Chinchar, V. G., Hyatt, A., Miyazaki, T. & Williams, T. (2009). Family Iridoviridae: poor viral relations no longer. Curr Top Microbiol Immunol 328, 123-170. [PubMed]

Grayfer, L., Edholm, E. S., Andino, F., Chinchar, V. G. & Robert, J. (2015). Ranavirus host immunity and immune evasion. In Ranaviruses: Lethal pathogens of ectothermic vertebrates, pp. 141-170. Edited by M. J. Gray & V. G. Chinchar. New York: Springer OPEN.

Hyatt, A. D., Gould, A. R., Zupanovic, Z., Cunningham, A. A., Hengstberger, S., Whittington, R. J., Kattenbelt, J. & Coupar, B. E. (2000). Comparative studies of piscine and amphibian iridoviruses. Arch Virol 145, 301-331. [PubMed]

Jancovich, J. K., Qin, Q., Zhang, Q. Y. & Chinchar, V. G. (2015a). Ranavirus replication:  Molecular, Cellular, and Immunological events. In Ranaviruses: Lethal pathogens of ectothermic vertebrates, pp. 105-139. Edited by M. J. Gray & V. G. Chinchar. New York: Springer OPEN.

Jancovich, J. K., Steckler, N. K. & Waltzek, T. B. (2015b). Ranavirus taxonomy and phylogeny. In Ranaviruses: Lethal pathogens of ectothermic vertebrates, pp. 59-70. Edited by M. J. Gray & V. G. Chinchar. New York: Springer OPEN.

Williams, T., Barbosa-Solomieu, V. & Chinchar, V. G. (2005). A decade of advances in iridovirus research. Adv Virus Res 65, 173-248. [PubMed]


References: Iridoviridae

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Citation: Iridoviridae

A summary of this ICTV Report chapter has been published as an ICTV Virus Taxonomy Profile article in the Journal of General Virology, and should be cited when referencing this online chapter as follows:

Chinchar, V.G., Hick, P., Ince, I.A., Jancovich, J.K., Marschang, R., Qin, Q., Subramaniam, K., Waltzek, T.B., Whittington, R., Williams, T., Zhang, Q., and ICTV Report Consortium. 2017, ICTV Virus Taxonomy Profile: IridoviridaeJournal of General Virology, 98, 890891.