1 Veterinary Medical Research Institute, Hungarian Academy of Sciences, PO Box 18, H-1581 Budapest, Hungary
2 Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E3
3 MRC Virology Unit, Institute of Virology, Church Street, Glasgow G11 5JR, UK
Correspondence
Gábor M. Kovács
gkovacs{at}vmri.hu
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ABSTRACT |
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The GenBank/EMBL/DDBJ accession number for the SAdV-1 DNA sequence reported in this paper is AY771780.
Present address: Department of Plant Anatomy, Eötvös Loránd University, Pázmány Péter sétány 1/C, H-1117 Budapest, Hungary.
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MAIN TEXT |
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Although numerous SAdV strains have been deposited in culture collections, most studies of adenovirus genomics have focused on HAdVs (especially HAdV-5). Corresponding work on SAdVs is very limited and commenced with restriction-endonuclease analyses (Dimitrov et al., 1979; Naroditsky et al., 1978
). Kidd et al. (1995)
described the most significant, and probably the only, comprehensive report dealing with the classification of SAdVs based on DNA sequences, namely those of the virus-associated (VA) RNA genes. Other studies not focusing specifically on SAdVs also employed SAdV sequences, such as those of the inverted terminal repetition (Bailey & Mautner, 1994
) or the E1A region (Avvakumov et al., 2002
, 2004
). For reasons associated with the development of alternative vector systems, interest in non-human primate adenoviruses has increased in recent years and has led to sequencing of the genomes of five chimpanzee adenoviruses (SAdV-21 to SAdV-25; Farina et al., 2001
; Roy et al., 2004
), which belong to recognized HAdV species (SAdV-21 to HAdV-B and the others to HAdV-E; Benk
et al., 2000
). The Old World monkey adenoviruses are phylogenetically more distant from the HAdV species, although they appear to have closer relationships to HAdV-A and HAdV-F (Bailey & Mautner, 1994
; Kidd et al., 1995
). Kovács et al. (2004)
reported the first complete genome sequence of an adenovirus isolated from an Old World monkey (SAdV-3). Phylogenetic analyses showed that this virus represents a lineage that branched at an early stage of primate adenovirus evolution and is related marginally more closely to HAdV-A and HAdV-F (which are also early lineages in primate adenovirus evolution) than to other HAdV species.
The purpose of the present work was to determine the genetic content and phylogenetic relationships of a monkey adenovirus with properties different from those of SAdV-3, as we presumed that such a virus would represent a distinct lineage. SAdV-1 was chosen because it was isolated from the tissues of a cynomolgus monkey (Macaca fascicularis), whereas SAdV-3 was isolated from rhesus monkey (Macaca mulatta) cells (Hull et al., 1956). Both viruses were classified as belonging to group 1 based on cytopathic effects (Hull et al., 1956
), but placed in different haemagglutination groups, with SAdV-1 in group 3 and SAdV-3 in group 2 (Rapoza, 1967
).
SAdV-1 was purchased from ATCC (VR-195) and propagated on rhesus macaque kidney cells (LLC-MK2). By using methods described by Kovács et al. (2004), viral DNA was isolated and sequenced via a random M13 library, and the genetic content and phylogeny of the completed sequence were analysed. Each nucleotide in the genome was determined an average of nine times and the entire sequence was obtained on both strands. The purity of the SAdV-1 DNA preparation was estimated at 50 % from the proportion of clones whose sequence matched that of the SAdV-1 genome.
Fig. 1 shows the genetic organization of SAdV-1. The genome (34 450 bp) is very similar in size to that of SAdV-3 (34 425 bp; Kovács et al., 2004
) and marginally larger than those of HAdV-40 (34 214 bp; Davison et al., 1993
) and HAdV-12 (34 125 bp; Sprengel et al., 1994
). These four viruses have the smallest genomes characterized thus far among the primate adenoviruses. The G+C content of the SAdV-1 genome is 55·21 mol%, which is almost the same as that of SAdV-3 (55·25 mol%) and different from those of HAdV-40 (51·22 mol%) and HAdV-12 (46·52 mol%). As in other adenoviruses, G+C content varies along the genome and shows the same pattern as SAdV-3, with the highest value in the pVII gene and the lowest in the E3 region (data not shown).
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In addition to the fiber and VA-RNA genes, adenovirus genomes exhibit the greatest organizational differences in the E3 and E4 regions (Davison et al., 2003; Ursu et al., 2004
). The SAdV-1 E3 and E4 regions each encode six genes corresponding to those in SAdV-3 (Kovács et al., 2004
), the same arrangement as in HAdV-A. HAdV-40 has a similar gene layout in the E3 and E4 regions, but lacks one gene in each region (E3 12.5K and E4 ORF1), presumably through loss after divergence from SAdV-1. E4 ORF1 has transforming properties and may have an anti-apoptotic role (Frese et al., 2003
; Leppard, 1997
), while the function of E3 12.5K is not known (Russell, 2000
).
During compilation of the genome sequence from random M13 clones, a deletion variant was identified. From the proportion of clones obtained, the mutant comprised approximately one-third of the genomes present in the DNA stock. The deletion spanned 659 bp (from nt 1138 to 1797) of the genome sequence, a region that contains the 3' end of E1A, the majority of E1B 19K and the overlapping 5' end of E1B 55K (Fig. 1). The presence of the mutant was confirmed by PCR analysis of the same stock of DNA used for sequencing, utilizing primers mapping in the regions flanking the deletion (data not shown). It is not known whether the mutant was present in the virus as originally isolated, or whether it was generated during passage in vitro. Mutants lacking sequences in the E1 region are often constructed in vitro specifically for development as vectors. It is possible that the SAdV-1 deletion mutant could be separated from parental virus by using an appropriate complementing cell line and utilized similarly.
Phylogenetic analyses were carried out for each SAdV-1 gene. Fig. 3 shows examples for the four genes employed for SAdV-3 by Kovács et al. (2004)
, each of which yielded relatively high bootstrap support. SAdV-1 fell generally into the earlier primate adenovirus branches, along with SAdV-3, HAdV-40 and HAdV-12. This pattern is in accordance with that reported previously for monkey adenoviruses on the basis of limited data (Bailey & Mautner, 1994
; Kidd et al., 1995
). SAdV-1 and HAdV-40 consistently formed a monophyletic group, and the gene arrangement in SAdV-1 is similar to that in HAdV-40, differing by retention of the two genes (E3 12.5K and E4 ORF1) that have been lost from HAdV-40. However, the two genomes share only approximately 70 % nucleotide identity. Phylogenetic analysis of the SAdV-1 fiber genes proved very sensitive to the parameters used, but was generally consistent with the proposition that the two genes arose by duplication in a common ancestor of SAdV-1 and HAdV-F, after this lineage had diverged from HAdV-A (Bailey & Mautner, 1994
).
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The genealogies shown in Fig. 3 raise questions regarding the origins of the monkey adenovirus and HAdV lineages. The apparently closer relationship between monkey adenoviruses and HAdV-F has led to the suggestion of a transfer between hosts (Tiemessen & Kidd, 1995
). Alternatively, it is possible that the earlier branches diverged in ancestral primates before the human lineage separated. Nonetheless, it seems likely that the genetic diversity of Old World monkey adenovirus species will turn out to be greater than that of HAdVs because of the longer evolutionary history of their hosts. This is likely to have an impact on the future of adenovirus taxonomy.
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ACKNOWLEDGEMENTS |
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Received 10 November 2004;
accepted 23 February 2005.
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