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Lloviu virus (LLOV) is the only currently classified cuevavirus. Like marburgviruses and possibly ebolaviruses, but unlike striaviruses and thamnoviruses, cuevaviruses infect bats. Cuevaviruses are notable for genomes expressing the ribonucleoprotein (RNP) complex-associated protein (VP24) and the RNA-dependent RNA polymerase (L) from a bicistronic mRNA rather than from individual transcripts (ebolaviruses, marburgviruses) (Negredo et al., 2011).
The morphology of cuevavirions has yet to be reported. Initial studies suggest that cuevavirions assume a filamentous, glycoprotein (GP1,2)-spiked morphology similar to that reported for ebolaviruses and marburgviruses (Maruyama et al., 2014).
Cuevavirus genomes are non-segmented, linear RNA molecules of negative polarity. The genomes are ≈19 kb (Negredo et al., 2011). Genomic RNA is likely uncapped and not polyadenylated.
Cuevaviruses express 7 structural proteins, all of which are homologous to those of ebolaviruses and marburgviruses. The second most abundant structural protein in virions is assumed to be the nucleoprotein (NP), which encapsidates the cuevavirus genome. The least abundant protein is assumed to be the RNA-dependent RNA polymerase (L), which mediates cuevavirus genome replication and transcription. The cuevavirus RNP complex likely consists of NP, VP24, polymerase cofactor (VP35), transcriptional activator (VP30), and L. These RNP complexes associate with the matrix protein (VP40), which lines the inner side of the virion membrane and GP1,2, which form globular spikes on the outside of the virion membrane. Similar to ebolaviruses, but unlike marburgviruses, cuevaviruses express GP1,2 via co-transcriptional editing and also express three soluble glycoproteins from the GP gene (sGP, ssGP, and Δ-peptide) (Negredo et al., 2011, Manhart et al., 2018).
Table 1.Cuevavirus. Location and functions of cuevavirus structural proteins.
RNP complex component; likely consists of two distinct functional modules; homo-oligomerizes to form helical polymers; binds to genomic and antigenomic RNA, VP35, VP40, VP30, and VP24
Nucleocapsid and cellular inclusion body formation; encapsidation of filovirus genome and antigenome; genome replication and transcription
(Manhart et al., 2018)
Polymerase cofactor (VP35)
RNP complex component; homo-oligomer; binds to double-stranded RNA, NP, and L
Replicase-transcriptase cofactor; inhibits interferon (IFN) regulatory factor 3 phosphorylation, IFN-α/β production, and protein kinase R phosphorylation
(Negredo et al., 2011, Manhart et al., 2018, Feagins and Basler 2015)
Matrix protein (VP40)
Likely consists of two distinct functional modules; homo-oligomerizes to form dimers and circular hexamers and octamers; binds single-stranded RNA, VP35; hydrophobic; membrane-associated; contains three late-budding motifs
Matrix component; regulation of genome transcription and replication; regulation of virion morphogenesis and egress
(Negredo et al., 2011)
Secreted glycoprotein (sGP)
Likely secreted as a parallel homo-dimer; likely N-glycosylated, C-mannosylated, sialylated
Spike glycoprotein (GP1,2)
Type I transmembrane and class I fusion protein; cleaved to GP1 and GP2 subunits that heterodimerize; mature protein is a trimer of GP1,2 heterodimers; inserts into membranes; heavily N- and O-glycosylated
Virion adsorption to filovirus-susceptible cells via cellular attachment factors; determines filovirus cell and tissue tropism; induction of virus-cell membrane fusion subsequent to endolysosomal binding to NPC1; inhibits innate immune response by interfering with tetherin
(Negredo et al., 2011, Ng et al., 2014, Maruyama et al., 2014, Brinkmann et al., 2016)
Secondary secreted glycoprotein (ssGP)
Nonstructural; secreted as a glycosylated monomer
Nonstructural; secreted; largely unstructured; likely O-glycosylated and sialylated
Hypothesized to suppress filovirus superinfection
(Radoshitzky et al., 2011)
Transcriptional activator (VP30)
RNP complex component; hexameric zinc finger protein; binds single-stranded RNA, NP, and L
Transcription initiation, reinitiaition, and antitermination
RNP complex-associated protein (VP24)
Likely RNP complex component; homo-tetramerizes; hydrophobic and membrane-associated
Regulation of genome transcription and replication; regulation of virion morphogenesis and egress; inhibits tyrosine phosphorylated STAT1 binding to karyopherin α5, STAT1 nuclear accumulation, and IFN-induced gene expression
(Negredo et al., 2011, Feagins and Basler 2015)
RNA-dependent RNA polymerase (L)
RNP complex component; homo-dimerizes; binds to genomic and antigenomic RNA, VP35, and VP30; mRNA capping enzyme
Genome replication and mRNA transcription; co-transcriptional editing
The cuevavirus genome has the gene order: 3′-NP-VP35-VP40-GP-VP30-VP24/L-5′ (Figure 1.Cuevavirus). The undetermined extragenic sequences at the extreme 3′ (leader) and 5′ (trailer) ends of the genome are assumed to be conserved and to be partially complementary. Genes are flanked by conserved transcriptional initiation and termination (polyadenylation) sites. The cuevavirus transcriptional initiation site sequence is identical to that of ebolaviruses but the transcriptional termination sequence is unique (3′-CUUCUU(A/G)UAAUU-5′). All cuevavirus genes overlap. Most of these overlaps are extremely short and limited to the highly conserved pentamer. Most genes possess relatively long 3′- and 5′-noncoding regions. Similar to ebolaviruses, but contrary to marburgviruses, the GP genes of cuevaviruses possess three overlapping open reading frames (ORFs) that can be joined through co-transcriptional polymerase stuttering (Negredo et al., 2011, Manhart et al., 2018).
Figure 1.Cuevavirus. Schematic representation of the cuevavirus genome organization. Genomes are drawn to scale. Courtesy of Jiro Wada, IRF-Frederick, Fort Detrick, MD, USA.
The replication strategy of cuevaviruses remains to be studied but is assumed to be highly similar to that of ebolaviruses and reminiscent of that of marburgviruses (Manhart et al., 2018). Cuevavirions are assumed to associate with attachment factors at the plasma membrane that mediate infection by endocytosis. Cuevavirus GP1,2 mediates cell surface C-type lectin binding and subsequent low pH-dependent fusion into endosomes. Cathepsin L cleavage is required for GP1,2 binding to the endosomal receptor Niemann-Pick disease, type C1 (NPC1) (Ng et al., 2014, Maruyama et al., 2014), which is also used by ebolaviruses and marburgviruses. Uncoating is presumed to occur in a manner analogous to that of other mononegaviruses. Cuevavirus transcription and genome replication likely take place in the cytoplasm and, in general, follow the models for members of the families Paramyxoviridae and Pneumoviridae. Transcription starts at the conserved transcriptional initiation site, and polyadenylation occurs at a stretch of uridine residues within the transcriptional termination site. The 5′-terminal non-coding sequences favor hairpin-like structures for all mRNAs. Replication involves the synthesis of full-length positive-sense copies (antigenomes) (Manhart et al., 2018). During infection, massive amounts of nucleocapsids are assumed to accumulate intracellularly and form intracytoplasmic inclusion bodies. Virions are likely released via budding from plasma membranes (Figure 3.Filoviridae).
Initial studies indicate that LLOV is antigenically distinct from other filoviruses (Maruyama et al., 2014).
Cuevaviruses were discovered in 2002 by next generation sequencing of samples taken from dead Schreibers’s long-fingered bats (Miniopterus schreibersii Kuhl, 1817) in Spain (Negredo et al., 2011). They were re-discovered in 2016 in dead Schreibers’s long-fingered bats collected in Hungary (Kemenesi et al., 2018).
The genus currently includes only a single species.
Cuevavirus: from Cueva del Lloviu, a cave in Asturias Principality, Spain, where LLOV was first discovered (Negredo et al., 2011).
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