1 School of Biology, Biomolecular Sciences Building, North Haugh, University of St Andrews, Fife KY16 9TS, UK
2 MRC Virology Unit, Institute of Virology, University of Glasgow, Church Street, Glasgow G11 5JR, UK
Correspondence
R. E. Randall
rer{at}st-and.ac.uk
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ABSTRACT |
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Present address: School of Biological Sciences, University of Liverpool, Liverpool L69 7ZB, UK.
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INTRODUCTION |
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SV5 has a single-stranded, non-segmented, negative-sense RNA genome of 15 246 nt (for isolate W3A), which contains seven genes that encode eight proteins [NP, P and V, M, F, SH, HN and L; for a review of the molecular biology of paramyxoviruses, see Lamb & Kolakofsky (2001)]. The ability to encode eight proteins from seven genes occurs because the V/P gene contains two overlapping open reading frames that give rise to two distinct gene products as a result of RNA editing. These two structural proteins are termed V and P and they have the first 164 aa of the N-terminus in common. However, as a consequence of RNA editing (resulting in the addition of two G residues at the editing site), the reading frames of the mRNAs that encode the two proteins differ past this point and the proteins thus have unique C-terminal domains (Thomas et al., 1988
). The P protein forms part of the viral polymerase complex, whilst the V protein is a multifunctional protein that: (i) blocks interferon (IFN) signalling by targeting STAT1 for proteasome-mediated degradation (Didcock et al., 1999a
, b
; Young et al., 2000
; Andrejeva et al., 2002
; Parisien et al., 2002
; Ulane & Horvath, 2002
); (ii) inhibits IFN production by an as yet uncharacterized mechanism (He et al., 2002
; Poole et al., 2002
; Wansley & Parks, 2002
); and (iii) binds to soluble, but not polymeric, NP and may thus have a role in the control of virus replication and encapsidation (Randall & Bermingham, 1996
).
The interaction of viruses with the IFN system is one of the critical factors that determine the outcome of acute virus infections (Stark et al., 1998; Goodbourn et al., 2000
; Levy & Garcia-Sastre, 2001
; Biron & Sen, 2001
; Sen, 2001
). However, there may be other more subtle consequences of the interaction of viruses with the IFN system. Thus, we have suggested that the ability of paramyxoviruses to establish persistent infections in vivo may be linked to their ability, or not, to block the IFN response (Chatziandreou et al., 2002
). The ability of viruses to circumvent the IFN response may also be one factor that limits their host range. For example, SV5 fails to block IFN signalling in mouse cells (Didcock et al., 1999a
) and is non-pathogenic in normal and severe combined immunodeficient (SCID) mice (Young et al., 1990
; Didcock et al., 1999a
). However, SV5 is lethal in STAT1-knockout mice, i.e. mice that cannot respond to IFN (He et al., 2001
, 2002
). Given the suggestion that IFN sensitivity may influence the ability of SV5 to establish persistent infections and that the sensitivity of paramyxoviruses to IFN may limit their host range (Didcock et al., 1999a
; Parisien et al., 2002
; Park et al., 2003
), we undertook this study to compare the ability of different human, simian, canine and porcine isolates of SV5 to block IFN signalling in human and dog cells. Furthermore, we cloned and sequenced both the P/V and F genes of these viruses to see whether there were obvious correlates of sequence diversity with the species from which they were isolated.
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METHODS |
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Cloning and sequencing of the V and F genes.
2fTGH or MDCK cells were infected or mock-infected with the appropriate isolate of SV5 and at 21 h post-infection (p.i.), the medium was replaced with serum-free medium. At 30 h p.i., this medium (containing progeny virus) was harvested, pelleted by ultracentrifugation (30 000 r.p.m. for 90 min in a Beckman SW50 rotor) and viral RNA was isolated by using a Qiagen RNeasy RNA extraction kit. cDNA was prepared from viral RNA by using reverse primers that were specific to the P/V or F gene (outside the coding regions) and Moloney murine leukaemia virus reverse transcriptase (Promega). The products of these reactions were used in PCRs with Pfu polymerase (Promega), using forward and reverse primers that were specific to either the P/V or F genes to generate full-length P/V and F gene products. These were then cloned into the pGATA (P/V) or pGEM T-Easy (F) vectors and sequenced by using an automated sequencer and internal oligonucleotides, to ensure that the sequence was covered in both directions.
Phylogenetic analysis.
Alignments of the sets of DNA sequences representing the F and V/P genes of isolates were made; for the latter, the two G residues that were introduced during synthesis of the P mRNA were included in each sequence. Phylogenetic analysis was carried out by using the program MrBayes 3 (Ronquist & Huelsenbeck, 2003), which applies Bayesian inference with Markov chain Monte Carlo techniques. From an input starting tree (chosen randomly in our application), the method involves successive perturbations of the current tree by a procedure picked stochastically from a range specifying different alterations in tree topology or branch-lengths, followed by a statistical test that is based on the fit of the input alignment to the new tree to decide whether to accept or reject that tree as the input for the next cycle of the process. The arrangements for choice of perturbation at each stage and for acceptance of the current tree are constructed in such a way that the output list of accepted trees should converge to represent the posterior probability distribution of trees contingent on the input alignment. A recent review of Bayesian methods in phylogenetic analysis is given by Huelsenbeck et al. (2001)
. By using standard options of the program, the general time-reversible model of nucleotide substitution was employed and rates of change across alignment sites were modelled by a discrete gamma distribution plus an invariant category. The sets of alignment loci that represented the first, second and third codon positions were assigned to separate partitions in the analysis. Each program run included one cold and three heated chains (the latter are a device to aid rapid convergence of the process) and proceeded for 2x106 generations, with sampling of trees every 100 generations. Each run started with a uniform prior distribution and a randomly chosen tree and, for each dataset, two runs with different starting trees were carried out to check convergence. The first 1001 trees of each run were discarded to allow the process to become stationary, leaving 19 000 trees for estimation of the probability distribution of trees contingent on the input alignment.
Detection of STAT1 by immunoblot analysis.
2fTGH or MDCK cells were infected with virus (m.o.i. 10) and incubated for 2429 h prior to lysis in sample buffer [0·05 M Tris/HCl (pH 7·0), 0·2 % SDS, 5 % 2-mercaptoethanol, 5 % glycerol]. Cellular polypeptides were separated by SDS-PAGE. The proteins were then transferred to PVDF membranes and treated sequentially with a polyclonal antibody against STAT1 (catalogue no. G16930; Transduction Laboratories) and a secondary anti-rabbit antibody coupled to horseradish peroxidase (Amersham Biosciences). The membrane was treated with ECL detection reagents (Amersham Biosciences) and exposed to X-ray film. Prior to lysis, the infected cells were examined by immunofluorescence to confirm that >95 % cells were infected.
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RESULTS |
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Phylogenetic analyses were carried out for the F and V/P genes by using the MrBayes 3 program. Independent runs for each dataset showed excellent convergence. Closely comparable results were obtained for both gene sets and only the results for the F gene are shown here. Fig. 2 shows the consensus tree obtained, in unrooted form. Most features in the tree were assigned maximum credibility values, with two lower values at central loci, indicating that the detail of branching in the core of the tree was not well-resolved. We presume that the root of the tree lies in or close to this central, unresolved region. On this basis, the isolates fell into five clades: (i) monkey and human isolates, except for cryptovirus; (ii) cryptovirus; (iii) German dog isolates CPI+ and CPI; (iv) pig isolate SER; and (v) Japanese and Scottish dog isolates.
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DISCUSSION |
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A primary reason for initiating these studies was to ascertain whether the host range of SV5 between dogs and humans might be restricted to the species from which they were isolated by their ability to block IFN signalling (Didcock et al., 1999a; Park et al., 2003
). However, apart from the previously documented case of CPI, which fails to block IFN signalling in either canine or human cells (Chatziandreou et al., 2002
), all the isolates tested degraded STAT1 in both human and canine cells. Thus, the few amino acid substitutions identified in the N-terminal domain of V did not inhibit the ability of V to block IFN signalling. Also, there did not appear to be a clustering of nucleotide or amino acid changes, which might have been indicative of selection pressure on V function in blocking IFN signalling in cells from different species. It was also of note that, apart from cryptovirus with an E206K change, no amino acid substitutions mapped to the C-terminal domain of V, although there were nucleotide changes that altered the amino acid sequence within the P-unique domain that were encoded by the same region of the V/P gene that encodes the unique C-terminal domain of V. This is presumably because few amino acid changes can be tolerated in the highly conserved, cysteine-rich C-terminal domain of V.
Overall, there was a surprising lack of sequence variation at both the nucleotide and amino acid level between the various isolates of SV5, even though they were isolated from different species and geographical regions over a period of approximately 30 years. Indeed, the level of variation was similar to that observed for measles H and mumps and HPIV3 HN proteins (van Wyke Coelingh et al., 1988; Rima et al., 1997
; Lim et al., 2003
), viruses whose host range is confined to man, and was significantly below that observed for the HN gene of Newcastle disease virus, a virus that infects many types of bird, including chickens and turkeys (Sakaguchi et al., 1989
). Within the F protein, in common with the porcine SER isolate, all of the canine isolates had an E132K change and, in common with both the porcine and cryptovirus isolates, also had M310I and S438T as well as S530 and R536 in their extended cytoplasmic tails. The canine viruses that were isolated in Glasgow (H221 and 78524) and Japan (T1) had I4R and A135V changes that were not found in the any of the other isolates, including CPI+, which was isolated from a dog in Germany. Interpretation of the SV5 trees based on nucleotide sequence comparisons of the P/V and F genes suggested that there are five lineages that emerge from the unresolved root. Interestingly, the Japanese T1 and Glasgow H221 and 78524 canine isolates appeared on the same branch as each other, but not with the German CPI canine viruses. In the placement of the root, the monkey (W3A and WR) and human bone-marrow viruses (but not cryptovirus) also formed a clade. Also consistent with this analysis, but as yet unproven, is the possibility that there is a division between the dog/pig and monkey/human isolates (Fig. 2
). Thus, there is clearly a requirement to sequence more variants of SV5 isolated from different species, in order to look more closely at underlying phylogenetic linkages.
From information published in the patent application relating to cryptovirus (WO02077211/EP1373477), it appears that this virus was a human isolate that may have come from a patient with neurological dysfunction. However, even though in the patent specifications it is claimed that this is a novel virus, this cryptovirus' did not show a significantly greater degree of difference from SV5 (2·25 % in F and 2·8 % in P) than any of the other isolates. None of the changes in cryptovirus, compared with W3A, were found in any of the human bone-marrow isolates (apart from those at aa 443 and 516 in F, which were common to all isolates, and 529, which was common to all isolates except WR), showing that, at least for the P and F proteins, there are no changes that might help to explain why these viruses were isolated from human tissues. With regard to the viruses that were isolated from human bone-marrow cells, they were clearly related most closely to each other. Thus, they all had the following changes: S178L in the P-unique domain, T3I, S19G, L498F and Q530 in the F protein and H533 and Q536 in the extended cytoplasmic tail. However, there were also several identifying nucleotide and amino acid differences among the various bone-marrow isolates. Thus, the LN isolate had two unique amino acid differences in the V/P proteins and two in the F protein, whilst the MIL isolate had two unique amino acid differences in the V/P proteins and the MEL isolate had a unique amino acid in the F protein, together with an extended cytoplasmic tail of only 5 aa, as opposed to 22 aa for all other isolates. The fact that they are clearly related more closely to each other may not be surprising, as they were isolated at roughly the same time and from the same geographical region (London). Similarly, the two Glasgow canine isolates are also clearly related more closely to each other than to the other isolates. However, the sequence variation between the bone-marrow isolates suggested strongly that the viruses were isolated independently of each other, thereby all but ruling out the possibility that they were laboratory contaminants (Goswami et al., 1984). If, as the weight of evidence now indicates, SV5 has been isolated regularly from bone-marrow cells in which the virus must presumably establish a persistent infection, then the reported isolation of SV5 from, or detection in, patients with a variety of diseases, including multiple sclerosis, subacute sclerosing panencephalitis (Robbins et al., 1981
), CreutzfeldtJakob disease (Horta-Barbosa et al., 1970
), pemphigus (Siegl & Hahn, 1969
), atherosclerosis (Behbehani et al., 1965
), Paget's disease (Basle et al., 1985
), hepatitis (Hsiung, 1972
; Liebhaber et al., 1965
) and the common cold (Schultz & Habel, 1959
), should not be dismissed lightly, especially as in many cases great effort was made to rule out the possibility of contamination (Robbins et al., 1981
; Goswami et al., 1984
). However, even if SV5 does cause persistent infections in humans, this does not necessarily mean that SV5 has a role to play in any human disease. Indeed, the wide spectrum of diseases from which SV5 has been isolated tends to argue against this. Furthermore, when examined in detail, as in the case of multiple sclerosis, the involvement of SV5 has been largely discounted. Nevertheless, if SV5 establishes persistent infections in a reasonable proportion of individuals, it may be timely to re-evaluate the role of SV5 and other paramyxoviruses in chronic human disease (Randall & Russell, 1991
), especially as we now have the tools to perform such studies more incisively. We also now know that SV5 and other paramyxoviruses interfere with cellular processes, including the IFN response and, thus, if there is a loss of cellular function in cells that are persistently infected with paramyxoviruses, the rationale behind any possible link with disease becomes easier to make.
The nomenclature of SV5 has always been problematic, given the repeated isolation of the virus over many years from numerous species. The problem is compounded because of a general assumption that if a virus is termed simian, then its natural host must be monkeys. To counter this assumption, new nomenclatures are creeping into use, such as SER virus and cryptovirus. However, these viruses are clearly no more different from the original W3A isolate than any of the other viruses we have examined. Furthermore, the virus is also often referred to as canine parainfluenza virus. Due to this confusion and reluctance by some authors to use the term SV5, we believe that it would be better to rename the virus parainfluenza virus 5 (PIV5), a nomenclature that was attempted in the late 1960s and early 1970s (Hsiung, 1972). At the time, this probably failed because it was suggested that SV5 should be classified as parainfluenza virus 2 (PIV2) of monkeys (Chanock et al., 1961
). However, we now know from extensive antigenic and sequence analysis that SV5 and PIV2 are distinct viruses. The advantage of using the term PIV5 is that isolates can be prefixed with nomenclature that refers to the species from which they were isolated, e.g. canine PIV5 or porcine PIV5. However, a potential problem with giving a prefix to an isolate arises where there is doubt as to whether the virus was genuinely isolated from a given tissue or whether it arose as a laboratory contaminant, for example from the use of primary monkey kidney cells in the isolation procedure. Indeed, the knowledge that SV5 can contaminate primary monkey kidney cells is often a reason why diagnostic laboratories discount any isolation of SV5 from human tissues (M. Zambon, Health Protection Agency, Colindale, London, UK; personal communication). However, given the availability of specific reagents to SV5, including mAbs, it should be relatively easy to screen cell lines for the presence of SV5 and thus exclude any possibility of laboratory contamination during the isolation procedure or, if the virus was isolated in primary monkey kidney cells, to go back to the original specimen and try to re-isolate the virus in cell lines that are guaranteed to be free of the virus. There is thus a need to undertake further, well-controlled attempts to isolate SV5 from various human tissues and to determine the incidence of human infection with this virus.
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ACKNOWLEDGEMENTS |
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Received 16 April 2004;
accepted 23 June 2004.