High-avidity human serum antibodies recognizing linear epitopes of borna disease virus proteins

Billich, Christian; Sauder, Christian; Frank, Ronald; Herzog, S.; Bechter, Karl; Takahashi, Kazuo; Peters, Helmut; Staeheli, Peter; Schwemmle, Martin

doi:10.1016/s0006-3223(02)01387-2

Cited by 67 publications

(53 citation statements)

References 24 publications

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“…A broad range of warm-blooded animals can be infected with BDV (1), and serological evidence suggests that BDV or a BDV-like virus also infects humans (9). Infection of newborn Lewis rats results in neurodevelopmental and behavioral abnormalities in the absence of inflammation, reminiscent of mood disorders, schizophrenia, and autism in humans (10).…”

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confidence: 99%

Genome trimming: A unique strategy for replication control employed by Borna disease virus

Schneider¹,

Schwemmle²,

Staeheli³

2005

Proc. Natl. Acad. Sci. U.S.A.

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Genome and antigenome synthesis of negative-strand RNA viruses is initiated at promoters located in inverted terminal repeats (ITR). The ITR of Borna disease virus (BDV), a persisting neurotropic virus with a nuclear replication phase, are exceptional in that they appear to be noncomplete. Our analysis showed that the vast majority of genomic and antigenomic RNA molecules of BDV lack four 5-terminal nucleotides required for perfect complementarity with the 3 ITR. By using a previously undescribed reverse genetics system, we investigated whether the structure of the ITR would affect virus propagation. BDV rescued from cDNA encoding complete ITR (rBDVc) showed wild-type virulence, whereas virus rescued from cDNA encoding a viral genome with noncomplete ITR (rBDVnc) was strongly attenuated. Both recombinant viruses expressed similar RNA and protein levels in persistently infected cells. However, rBDVnc particles were less infectious, indicating that complete ITR are required for high viral replicase but not transcriptase activity. Interestingly, genomic RNA from purified rBDVc particles lacked 5-terminal nucleotides like authentic BDV, strongly suggesting programmed genome truncation. By specifically trimming its genome at the 5 terminus, BDV seems to limit viral genome amplification, which may favor noncytolytic viral persistence.genome truncation ͉ viral RNA termini ͉ viral persistence ͉ neurotropic B orna disease virus (BDV) can persist in cultured cells as well as in neurons and some other brain cells of infected animals without causing a cytopathic effect (1-3). On the basis of several unique genetic and biological properties, BDV has been classified into a separate virus family (Bornaviridae) in the order Mononegavirales. It is an enveloped neurotropic virus with a nonsegmented, negative-strand RNA genome (4). The genome of BDV is replicated and transcribed in the nucleus of infected cells (5, 6). To achieve a balanced expression of the six viral proteins from only three transcription units, BDV employs a variety of strategies that include the use of overlapping ORFs, read-through of transcriptional signals, and alternative splicing of polycistronic transcripts (7,8).A broad range of warm-blooded animals can be infected with BDV (1), and serological evidence suggests that BDV or a BDV-like virus also infects humans (9). Infection of newborn Lewis rats results in neurodevelopmental and behavioral abnormalities in the absence of inflammation, reminiscent of mood disorders, schizophrenia, and autism in humans (10). In contrast, infection of adult Lewis rats frequently induces an immunemediated neurological disorder (11), characterized by partial ataxia of the hind legs, uncoordinated movement, and massive weight loss. BDV thus provides an important model for studying mechanisms of viral persistence and immune-mediated CNS pathology as well as for the development of virus-induced neuropsychiatric disease.Because of the multiplication strategy of negative-strand RNA viruses, their naked genomic RNA by itself is no...

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confidence: 99%

Genome trimming: A unique strategy for replication control employed by Borna disease virus

Schneider¹,

Schwemmle²,

Staeheli³

2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Serologic and molecular epidemiological data indicate that the natural host range of BDV as well as its prevalence and geographic distribution are very broad (19,20,(35)(36)(37)43). Moreover, there is evidence that BDV can infect humans, being possibly associated with certain neuropsychiatric disorders (2,5,31,(35)(36)(37)43).BDV is an enveloped virus with a nonsegmented, negativestrand RNA genome. Its genome (ca.…”

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Functional Characterization of the Genomic Promoter of Borna Disease Virus (BDV): Implications of 3′-Terminal Sequence Heterogeneity for BDV Persistence

Rosario

Perez

Torre

2005

J Virol

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Borna disease virus (BDV) is an enveloped virus with a genome organization characteristic of Mononegavirales. However, based on its unique features, BDV is considered the prototypic member of a new virus family, Bornaviridae, within the order Mononegavirales. We have described the establishment of a reverse genetics system for the rescue of BDV RNA analogues, or minigenomes, that is based on the use of polymerase I/polymerase II. Using this BDV minigenome rescue system, we have examined the functional implications of the reported sequence heterogeneity found at the 5 and 3 termini of the BDV genome and also defined the minimal BDV genomic promoter within the 3-terminal 25 nucleotides. Our results suggest that the accumulation of RNA genome species containing truncations of one to three nucleotides at their 3 termini may contribute to modulate BDV RNA replication and gene expression during long-term persistence.Borna disease virus (BDV) causes central nervous system disease in a variety of vertebrate species, which is frequently manifested by behavioral abnormalities (20,33,37). However, both viral and host factors can influence symptoms and pathology associated with BDV infection (18-20, 35, 37, 43). Serologic and molecular epidemiological data indicate that the natural host range of BDV as well as its prevalence and geographic distribution are very broad (19,20,(35)(36)(37)43). Moreover, there is evidence that BDV can infect humans, being possibly associated with certain neuropsychiatric disorders (2,5,31,(35)(36)(37)43).BDV is an enveloped virus with a nonsegmented, negativestrand RNA genome. Its genome (ca. 8.9 kb), the smallest among known nonsegmented, negative-strand RNA viruses, has an organization similar to that of other mononegaviruses (12,40). Six major open reading frames are found in the BDV genome sequence (3Ј-N-p10/P-M-G-L-5Ј) (12,40). BDV has the property, unique among known animal nonsegmented, negative-strand RNA viruses, of a nuclear site for the replication and transcription of its genome (3, 9). Moreover, BDV uses a remarkable diversity of strategies, including RNA splicing, for the regulation of its genome expression (10,12,40,41,45). Based on its distinct features among known mononegaviruses, BDV is considered the prototypic member of a new virus family, Bornaviridae, within the order Mononegavirales.We have established an RNA polymerase I/polymerase II system for intracellular reconstitution of BDV RNA replication and transcription (30). In this system, a BDV RNA analog, or minigenome, is intracellularly synthesized by the cellular RNA polymerase I. This BDV minigenome RNA contains the BDV 5Ј and 3Ј untranslated regions cis-acting sequences required for RNA synthesis mediated by the BDV polymerase (30,39,40,42). Encapsidation of the polymerase I-derived BDV minigenome RNA by plasmid-supplied BDV N and P generates a template that is recognized by the intracellularly reconstituted BDV polymerase to direct synthesis of fulllength antiminigenome RNA (replicate) and a subgenomic mRNA (transcri...

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“…Dependent on host and age, BDV infection can result in symptomless viral persistence or severe immune-mediated neurological disease (20). Seroepidemiological surveys suggest that BDV or a related virus can infect humans (21), although the association with specific diseases awaits further clarification. The viral genome includes six open reading frames (ORFs) encoding N, X, P, matrix protein (M), glycoprotein (G), and L (22,23).…”

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Overlap of Interaction Domains Indicates a Central Role of the P Protein in Assembly and Regulation of the Borna Disease Virus Polymerase Complex

Schneider

Blechschmidt

Schwemmle

et al. 2004

Journal of Biological Chemistry

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The active polymerase complex of Borna disease virus is composed of the viral proteins N, P, and L. The viral X (negative regulatory factor) protein acts as a regulator of polymerase activity. Interactions of P with N and X were previously studied, but interactions with L were poorly defined. Using a mammalian two-hybrid system, we observed that L specifically interacts with P but not with N, X, or itself. Mapping of the L-binding domain in the P molecule revealed that it overlaps with two adjacent domains required for multimerization and interaction with N. Competition experiments showed that the interaction between L and P was inefficient when N was present, indicating that L may preferentially interact with free P in infected cells. Interestingly, a multimerization-defective P mutant maintained the ability to interact with L, N, and X but failed to support reporter gene expression from an artificial Borna disease virus minigenome. Furthermore, dominant negative effects on minigenome activity were only observed when P mutants with an intact multimerization domain were used, suggesting that P multimers, rather than monomers, exhibit biological activity. P mutants lacking functional interaction domains for L or N still formed complexes with these viral proteins when wild-type P was available as a bridging molecule, indicating that P multimers have the potential to act as scaffolds on which the RNA polymerase complex is assembled.The active transcription and replication complex of non-segmented negative strand RNA viruses, termed ribonucleoprotein complex (1), consists of the viral polymerase (L), 1 the phosphoprotein (P), the nucleoprotein (N), and the viral RNA (2). P is a co-transcriptional factor of L, whereas N encapsidates the viral genome to form N⅐RNA complexes (3). For Sendai virus, a prototype paramyxovirus, it was shown that P acts as a scaffold protein, which brings L into close proximity to the N⅐RNA complex (4), thus allowing RNA synthesis. In the absence of P, the N⅐RNA complexes are not recognized by L (5). The viral P protein exerts this scaffolding function by employing independent binding sites for L and the N⅐RNA complex (6). P of Sendai virus contains an additional but distinct binding domain for free N (not bound to viral RNA) (7) and a domain required for multimer formation (8, 9). Complex formation between P and free N prevents aggregation of N (7). Oligomerization is an essential prerequisite for Sendai virus P function in viral transcription and replication (4). The precise function of oligomeric P is unclear. It is assumed that oligomer formation facilitates movement of P (and most likely of the complete polymerase complex) on the RNA template, thereby maintaining polymerase processivity (4). A requirement of P oligomers for viral RNA synthesis was also described for P proteins of other viruses of the order Mononegavirales, including vesicular stomatitis virus (10, 11) and human parainfluenza virus type 3 (12). For the P protein of Sendai virus and human parainfluenza virus type 3, a de...

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High-avidity human serum antibodies recognizing linear epitopes of borna disease virus proteins

Cited by 67 publications

References 24 publications

Genome trimming: A unique strategy for replication control employed by Borna disease virus

Genome trimming: A unique strategy for replication control employed by Borna disease virus

Functional Characterization of the Genomic Promoter of Borna Disease Virus (BDV): Implications of 3′-Terminal Sequence Heterogeneity for BDV Persistence

Overlap of Interaction Domains Indicates a Central Role of the P Protein in Assembly and Regulation of the Borna Disease Virus Polymerase Complex

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