Mented, Negative-Strand RNA Virus
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ウ イ ル ス 45(2),165-174,1995 特集 ネガテ ィブ鎖RNAウ イルス 4. The atypical strategies used for gene expression of Borna disease virus, a nonseg- mented, negative-strand RNA virus. ANETTE SCHNEEMANN,* PATRICK A. SCHNEIDER,*•˜ and W. IAN LIPKIN*•˜ *Laboratory for Neurovirology , Department of Neurology, Department of Anatomy and Neurobiology, § Department of Microbiology and Molecular Genetics , University of California-Irvine, Irvine, CA 92717 $ To whom correspondence should be addressed . FAX : (714) 824-2132. Email : ilipkin @ uci. edu al., 1992), has opened the fields of BDV biology and Abstract pathogenesis for rigorous investigation. BDV has Borna disease virus (BDV) is a neurotropic agent now been defined as an enveloped, nonsegmented that causes disturbances in movement and behavior negative-strand RNA virus (Briese et al., 1992 ; in vertebrate host species ranging from birds to Compans et al., 1994 Zimmermann et al., 1994) and primates. Although the virus has not been isolated its sequence has been determined independently in from human subjects, there is indirect evidence to two laboratories (Briese et al., 1994 ; Cubitt et al., suggest that humans with neuropsychiatric dis- 1994b). Although aspects of gene organization and orders may be infected with BDV. Recently, virus deduced protein sequence suggest relatedness to particles have been isolated and the viral genomic members of the order Mononegavirales (paramyx- RNA has been cloned. This analysis revealed that oviruses, rhabdoviruses and filoviruses), BDV BDV is a nonsegmented, negative-strand RNA shows unusual features such as RNA splicing virus. Unusual features such as RNA splicing, over- (Schneider et al., 1994 ; Cubitt et al. 1994c) and lap of transcription units and transcription signals, overlap of transcription units and transcription as well as sequence dissimilarity for four of five signals (Schneemann et al., 1994). These features major open reading frames to genes of other nonseg- indicate that BDV is likely to represent a previously mented, negative-strand RNA viruses suggest that unrecognized genus or family within this order. BDV is likely to represent a new taxon within the Originally considered to be a natural infection of order Mononegavirales. horses and sheep in Southeastern Germany, infec- tion has now been reported in cats, cattle and birds Introduction in Europe, North America and Africa. (Lundgren The neurologic syndrome known as Borna dis- and Ludwig, 1993 ; Kao et al., 1993 ; Malkinson et ease (BD) was first described approximately 200 al., 1993 ; Caplazi et al., 1994). It is not known years ago (Abildgaard, 1785). The agent respon- whether this apparent extension in host and geo- sible for the disease, Borna disease virus (BDV), graphic range represents improved survey methods remained elusive for many years due to its low level or spread of BDV to new species and locations. The of replication in infected hosts. The identification of potential host range is still larger. In addition to the BDV cDNA clones by subtractive hybridization natural hosts already described, rodents, rabbits and (Lipkin et al., 1990) and more recently the advent of primates are readily infected experimentally a method for isolation of virus particles (Briese et (Ludwig et al., 1988). Whether BDV naturally 166 ANETTE SCHNEEMANN,* PATRICK A. SCHNEIDER,*•˜ and W. IAN LIPKIN*•÷•˜•ö infects humans is controversial. Serum antibodies to 1989 ; Carbone et al., 1991). BDV have been detected in patients with depression Genomic organization or schizophrenia and monocytes from some of these patients were found to contain viral proteins (Bode Two laboratories have recently cloned and se- et al., 1988 ; Fu et al., 1993 ; Rott et al., 1985). quenced BDV genomic RNA using template from However, there are no confirmed reports of virus ribonucleoproteins (strain He-80) (Cubitt et al., isolation from humans and thus the question of 1994a, 1994b) or virus particles (strain V) (Briese whether BDV can be implicated in human disease et al., 1994). Each reported a genome of approxi- remains open. mately 8,900 nt with complementary termini, encod- Infection results in an immune-mediated progres- ing 5 major open reading frames (ORF's). ORFs I, sive movement disorder (Narayan et al., 1983 ; II, III, IV and V identified by Cubitt et al. are Solbrig et al., 1994, 1995). This disorder has been similar to ORFs p40, p23, gpl8, p57 and p180 (pol) linked in a rat model of experimental infection to identified by Briese et al., respectively, with the disturbances in brain dopamine (DA) systems following exceptions : (1) ORFs I, II, III, IV and V (Solbrig et al., 1994, 1995). Early in disease, animals are in frame with one another whereas p57 is in a + show hyperactivity and exaggerated startle 1/-2 frame relative to the other ORFs in Briese et responses. Later, they begin to display repetitive al.'s sequence ; (2) ORF IV predicts a protein of 40 stereotyped motor behaviors, unusual postures of kDa vs. the 57 kDa protein predicted by ORF p57. limbs and trunk as well as self-mutilation. These These differences have now been reconciled to features are reminiscent of human neuropsychiatric confirm the genomic organization proposed by conditions associated with DA abnormalities like Briese et al. for both viral strains (Cubitt et al., 1994- schizophrenia, post-encephalitic Parkinsonism and c). tardive dyskinesia. Infected animals show enhanced Gene products have only been identified for ORFs behavioral sensitivity to drugs that serve as direct p40 (I), p23 (II) and gpl8 (III) (Mc Clure et al., or indirect agonists of DA receptors (DA 1992 ; Thierer et al., 1992 ; Kliche et al., 1994, agonists) ; conversely the movement and behavior Schadler et al.,1985) . The position of ORFs p40 and disorder is improved following treatment with drugs p23 on the antigenome and features such as mol. wt., that selectively block some classes of DA receptors charge and abundance of the respective proteins in (DA antagonists) (Solbrig et al., 1994, 1995). Still infected cells, as well as the presence of posttrans- later in disease, chronically infected animals may lational modifications (p23 is phosphorylated) become blind from retinopathy, or obese due to (Thiedemann et al.,1992) , suggest that p40 encodes hypothalamic disturbances. As in infections with the viral nucleoprotein (N) and p23 the phospho- other neurotropic agents, such as rabies virus or protein (P). The gpl8 (III) ORF encodes a 18 kDa herpes simplex virus, inoculation into a limb results glycoprotein (Kliche et al.,1994) , while the equiva- in centripetal transsynaptic transport to the CNS lent ORF in other nonsegmented, negative-strand (Carbone et al.,1987) . Olfactory inoculation is more RNA viruses directs synthesis of a non-glycosylated efficient and is presumed to be the route of natural matrix protein (M) (Banerjee, 1991). Glycosylated infection. Expression of the movement and behavior M proteins that resemble gpl8 in size and pI (pI 10) disorder is dependent upon an intact host immune have also been found in coronaviruses, which syn- response since immunosuppression prevents these thesize a 20 kDa glycoprotein with a pI of 10 disturbances in adult-infected animals (Narayan et (Armstrong et al., 1984). There is preliminary evi- al., 1983). Animals infected as neonates do not dence that gpl8 is present in the virus envelope and mount a cellular immune response to the virus but that it may serve as a viral attachment protein develop a disease characterized by hyperactivity (Kliche et al.,1994) . Computer analysis of ORF p57 and subtle learning disturbances (Dittrich et al., (IV) revealed 14 potential N-glycosylation sites as The atypical strategies used for gene expression of Borna disease virus, a nonsegmented, negative-strand RNA virus. 167 well as N-terminal and C-terminal hydrophobic least six primary, polyadenylated RNAs with appar- anchor domains (Briese et al.,1994) . Therefore, it is ent lengths of 0.8 kb, 1.2 kb, 1.9 kb, 2.8 kb, 3.5 kb likely that this gene directs expression of the BDV and 7.1 kb (Briese et al., 1994, Cubitt et al., 1994b) . glycoprotein (G). The most 3' ORF on the viral An additional RNA of 4.7 kb has been reported by antigenome, pol (V), encompasses more than half Cubitt et al. The abundance of these RNAs in infect- of the genome and contains motifs considered criti- ed cells and tissues is consistent with the 3'-to-5' cal to viral RNA polymerase activity (Briese et al., transcriptional gradient found for other nonseg- 1994 ; Cubitt et al., 1994b). Cubitt et al. predicted a mented, negative-strand RNA viruses. Two of the protein of 170 kDa from ORF V. However, the primary transcripts, the 7.1 kb RNA and the 2.8 kb presence of conserved sequences between strain V RNA, have been shown to be posttranscriptionally and strain He80 upstream of the AUG colon of ORF modified by RNA splicing to yield at least two V, as well as analysis of viral transcripts (see additional RNA species, 6.1 kb and 1.5 kb in length below) suggests that pol is expressed from two (Schneider et al., 1994 ; Cubitt et al., 1994c). separate exons to yield a protein of 190 kDa. Addi- BDV subgenomic RNAs were initially mapped to tional smaller ORFs with coding capacities of less the antigenome by Northern blot hybridization in than 16 kDa have been identified on both the posi- two separate laboratories (Briese et al., 1994 ; tive (antigenomic) and negative (genomic) RNA Cubitt et al., 1994b) (figure 1). This analysis strands (Briese et al., 1994 ; Cubitt et al., 1994b). revealed a complex pattern of overlapping tran- Whether any of these ORFs is expressed is un- scripts that included several polycistronic RNAs. known. The results obtained by the two groups differed with respect to the location of the 2.8 kb RNA, the Transcription of the BDV genome 1.5 kb RNA and 6.1 kb RNA.