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1 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
2 Central Laboratory, Guangzhou Children's Hospital, Guangzhou 510120, China
3 South China Sea Institute of Oceanology, LED, Chinese Academy of Sciences, Guangzhou 510301, China
4 Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, China
Correspondence
Chuyu Zhang
Zhang_whu{at}yahoo.com.cn
Rong Zhou
zhou3218{at}yahoo.com
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTS AND DISCUSSIONREFERENCES |
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The GenBank/EMBL/DDBJ accession numbers for the human adenovirus type 3 strain GZ1 and GZ2 sequences reported in this paper are DQ099432 [GenBank] and DQ105654 [GenBank] , respectively.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTS AND DISCUSSIONREFERENCES |
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; Farkas et al., 2002; Kovács et al., 2003). They can be divided into four genera, Atadenovirus, Aviadenovirus, Mastadenovirus, Siadenovirus, and unassigned species (Benk
et al., 2000, 2002; Shenk, 2001; Davison et al., 2003; Kovács et al., 2003). Since the first human adenovirus (HAdV) was isolated (Rowe et al., 1953), 51 different HAdV serotypes have been identified within the genus Mastadenovirus and they can be classified into six species (HAdV-A to -F) based on a variety of parameters, including oncogenicity in rodents, electrophoretic mobility (Wadell, 1979) and DNA or genome identity (Garon et al., 1973; Green et al., 1979; Wadell et al., 1980; Wadell, 1984; De Jong et al., 1999), as well as the classical gold standards of serum neutralization and haemagglutination-inhibition tests (Davison et al., 2003).
HAdV-B species have been divided further into two groups: B1, including HAdV-3, -7, -16, -21 and -50, and SAdV-21; and B2, including HAdV-11, -14, -34 and -35 (Wold et al., 1979; Stone et al., 2003). HAdV-B group B1 viruses have been isolated from patients with febrile respiratory disease, especially fatal acute respiratory disease (ARD) (Hierholzer, 1995; Erdman et al., 2002). Members of group B2, with the exception of HAdV-11a and -14 (Van der Veen, 1963; Mei et al., 1998), are associated with persistent infections of kidney and urinary tract (Myerowitz et al., 1975; Shields et al., 1985).
Of the 51 HAdV serotypes, about one-third are associated with human diseases. Adenovirus infections can occur endemically or as outbreaks. HAdV-B group B1 (HAdV-3, HAdV-7 and, less frequently, HAdV-21) and HAdV-4 have been the causative agents in epidemic outbreaks of respiratory disease in Europe, America, Oceania and Asia (Herbert et al., 1977; Martone et al., 1980; Lewis et al., 2004; Frantzidou et al., 2005). Viruses of group B1 (HAdV-3, -7 and -21) can occasionally infect tissues of the central nervous system and cause aseptic meningitis, meningoencephalitis and encephalitis (Chany et al., 1958; Faulkner & Van Rooyen, 1962; Similä et al., 1970).
Epidemic outbreaks of ARD caused by HAdV-4 and HAdV-7 among American and Canadian basic military trainees have been controlled by the introduction of effective live enteric-coated oral vaccines since the 1970s (Dudding et al., 1972); however, the manufacture of HAdV vaccines was discontinued in 1996. HAdV-3, first isolated by investigators in the Walter Reed Army Institute of Research from patients with ARD at Fort Leonard Wood (MO, USA) in the winter of 1952–1953 (http://history.amedd.army.mil/booksdocs/historiesofcomsn/section1.htm), is widely prevalent all over the world (Herbert et al., 1977; Martone et al., 1980; Ryan et al., 2002; Frantzidou et al., 2005), especially in Asia (Itakura et al., 1990; Itoh et al., 1999; Hong et al., 2001; Kim et al., 2003; Li et al., 2004). However, no efficient vaccine against HAdV-3 has been developed. HAdV infections are highly contagious and common in dense and close populations, such as military training venues and day-care centres. The population of Asia is large and often dense, especially in China and Japan. Consequently, epidemics of ARD caused by HAdVs occur at high frequency. In July 2004, more than 200 children from an infant school were infected with HAdV-3 in Guangzhou, southern China (Zhu et al., 2005).
In Asia, multiple HAdV-3 genome types have been identified by restriction-enzyme analysis (Itakura et al., 1990; Itoh et al., 1999; Kim et al., 2003). In China, the dominant genome type from 1962 to 1988 was HAdV-3a2, with occasional isolates of HAdV-3a4, HAdV-3a5 and HAdV-3a6 (Li & Wadell, 1988; Li et al., 1996). In Japan, the dominant genome type from 1983 to 1991 was HAdV-3a, with occasional isolates of HAdV-3a8 and HAdV-3c (Itakura et al., 1990; Mizuta et al., 1994; Shiao et al., 1996). In Seoul, Korea, six new variants, HAdV-3a13 to HAdV-3a18, were found from 1990 to 2000 (Kim et al., 2003). Genome types may vary by location and time of isolation; some genome types may be associated with greater virulence (Kajon et al., 1990, 1996). It is therefore important to understand the genomics and bioinformatics of human disease-relevant HAdVs of group B1.
Since the first HAdV genome sequence was reported (HAdV-2) (Roberts et al., 1984, 1986), the complete genome sequences of 21 members of the genus Mastadenovirus have been released, with at least one from each species. For HAdV-B, to date, genomes of HAdV-7, -11, -21, -35 and -50 have been deposited in GenBank/EMBL (Gao et al., 2003; Mei et al., 2003; Stone et al., 2003; Vogels et al., 2003; Roy et al., 2004; Purkayastha et al., 2005). The complete genomic sequence of HAdV-3 has not been reported previously. In this report, two complete and annotated genome sequences of HAdV-3a, strains Guangzhou01 (GZ1) and Guangzhou02 (GZ2), are described (GenBank accession nos DQ099432
[GenBank]
and DQ105654
[GenBank]
, respectively); open reading frames and non-coding motifs were also analysed and compared.
Strain GZ1 infection produced a typical cytopathic effect (CPE), whereas strain GZ2 did not. The genome organization of both strains is similar to that observed in other members of HAdV-B. Bioinformatics provides an insight into the biology of HAdV-3 and raised our interest in the CPE difference caused by the two strains. The clinical application of HAdV-2- and HAdV-5-based gene-transfer vectors has been hampered because of pre-existing immunity against HAdV-2 and HAdV-5, which could affect the efficacy and even safety of adenovirus vector administration. HAdV-3, unlike HAdVs that do not belong to HAdV-B, has no proven affinity for the coxsackievirus–adenovirus receptor (CAR) (Roelvink et al., 1998). This receptor diversity implies that HAdV-3 has a different tropism from CAR-interacting AdVs and could provide an alternative to HAdV-5-based gene-transfer vectors (Havenga et al., 2002; Sirena et al., 2004).
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTS AND DISCUSSIONREFERENCES |
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). Type-specific primers designed to the hypervariable regions (HVRs) of the HAdV hexon were also utilized to correctly identify HAdV-3, -4, -7 and -11. The following primers were used: HAdV-3-specific, HAdV-3S (5'-AAGACATTACCACTACTGAAGGAGAAG-3') and HAdV-3A (5'-CGCTAAAGCTCCTGCAACAGCA-3'); HAdV-4-specific, HAdV-4S (5'-GGTAGCTGCCATGCCAGGTG-3') and HAdV-4R (5'-CATAGTTAGGAGTGGCGGCGG-3'); HAdV-7-specific, HAdV-7S (5'-GGGAAAGACATTACTGCAGACAAC-3') and HAdV-7R (5'-GGCGAAAAAGCGTCAGCAG-3'); and HAdV-11-specific, HAdV-11S (5'-AGGAACACGTAACAGAAGAGGAAACC-3') and HAdV-11R (5'-TAGCTTCGGAACTTGTGTCTTCTGTT-3').
Preparation of viral DNA and genome-type analysis.
Virus was propagated in HEp-2 cells and viral DNA was extracted by using a previously described method (Shinagawa et al., 1983). Purified HAdV genome DNA was digested by restriction enzymes (BamHI, EcoRI, HindIII, SalI and SmaI; TaKaRa). HAdV strains were genome-typed by comparing the restriction profiles with those of prototype and other genome types described in the literature and according to the genome-type denomination system (Li & Wadell, 1988; Golovina et al., 1991; Li et al., 1996; Kim et al., 2003).
DNA cloning and sequencing.
The restriction fragments of HAdV genome DNA digested with HindIII, EcoRI, BamHI or SmaI were purified with QIAquick Gel Extraction kits (Qiagen) and cloned into pBlueScript SK(+) vectors. The entire HAdV-3 genome DNA was resequenced using primers from initially sequenced regions cloned in vectors and various HAdV-3 gene sequences archived in GenBank/EMBL. Template DNA (0.1–1.0 µg per reaction) was further purified by passing through Mini Spin Columns (Qiagen). The sequencing reaction was carried out by using an ABI Prism BigDye Terminator v3.1 Cycle Sequencing Ready Reaction kit with AmpliTaq DNA polymerase on an ABI 3730 DNA sequencer (Applied Biosystems). All of the reported sequences are the result of at least three sequencing reactions.
Direct sequencing of inverted terminal repeat (ITR) ends.
The 5' and 3' ends of the linear HAdV-3 genome were sequenced directly on an ABI 3730 DNA sequencer (Applied Biosystems) with the repurified genomic DNA as templates. Primers were designed from newly obtained internal sequences.
Genome annotation and sequence analysis.
The sequences were assembled with SEQMAN software from the lasergene package (dnastar) and SEQUENCHER 4.1.4 (Gene Codes). Genome annotation provided an additional layer of sequence quality control. Unresolved and ambiguous sequences were resequenced with primers close to the regions in question.
General features of the HAdV-3 genome sequences were revealed by using the University of Wisconsin Genetics Computer Group (GCG) package (SEQWEB v. 2). The genome sequence was annotated with the annotation protocol used for HAdV-1 genome analysis (Lauer et al., 2004) by first dividing the sequence into contiguous 1 kb non-overlapping segments. Briefly, these segments were queried systematically against the non-redundant NCBI database using the program BLASTX of the BLAST suite of sequence-alignment software (Altschul et al., 1990). Default parameters of word size=3 and expectation=10, with the BLOSUM62 substitution matrix and with gap penalties of 11 (existence) and 1 (extension), were applied to these analyses. Low-complexity sequences were filtered out of the queries, as per the BLAST algorithm.
GENSCAN 1.0 and GENOMESCAN were used for theoretical gene predictions (Yeh et al., 2001). They were useful for identifying exons from the coding sequences where exon–intron borders were difficult to determine. Other splice site-finder programs [WISE2 (http://www.ebi.ac.uk/Wise2/advanced.html) and SPLICEPREDICTOR (Brendel & Kleffe, 1998)] were used to find splice-donor and -acceptor sites with the highest score. In parallel, novel sequences or ‘hypothetical proteins' were also identified by using FGENESV, software for predicting potential genes in viral genomes (http://www.softberry.com/berry.phtml?topic=index&group=programs&subgroup=gfindv) and GENEMARK v. 2.4, a Hidden Markov method-based gene-prediction software (Besemer & Borodovsky, 1999). In these annotations, although FGENESV had a slightly higher accuracy than the others, none of them were completely comprehensive or accurate in predicting putative genes. To visualize the annotation progress, the genome-annotation and -editor tool ARTEMIS was used to expedite genome annotation (Berriman & Rutherford, 2003).
Whole-genome alignment and comparisons of the sequences from HAdVs were performed by using the dot-plot software Advanced PipMaker (http://pipmaker.bx.psu.edu/cgi-bin/pipmaker?advanced), which aligns long genomic DNA sequences quickly and with good sensitivity (Schwartz et al., 2000).
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RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTS AND DISCUSSIONREFERENCES |
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General characteristics of the HAdV-3 genome sequence
The genome sequences of HAdV-3 strains GZ1 and GZ2 were annotated to identify biological features. This was facilitated by using reference genomes from the recently determined HAdV-11 (GenBank/EMBL accession nos AF532578
[GenBank]
and AY163756
[GenBank]
) and HAdV-7 (GenBank/EMBL accession nos AY594255
[GenBank]
and AC_0 00018) prototype strains. Like other members of the genus Mastadenovirus, the HAdV-3 genome is organized into early, intermediate and late transcription regions (Fig. 1). The strain GZ1 genome was 35 273 bp in length and had an overall base composition of 25.36 % A, 25.69 % C, 25.31 % G and 23.64 % T. The G+C content (51.0 mol%) was within the 50–52 mol% range noted in the literature for HAdV-B (Jin, 2001). Strain GZ1 DNA had an Mr of 2.1x107, determined from its base composition. The strain GZ2 genome was 35 269 bp in length and had nearly the same composition as strain GZ1. Thirty-nine protein-coding sequences and two RNA-coding sequences were identified in the genome sequences of both strains, including the pX protein (with predicted molecular masses of 8.3 kDa in strain GZ1 and 7.6 kDa in strain GZ2). Functionally, other non-coding features, such as promoters and transcription factor-binding and -recognition sites, were conserved between the two strains, as shown in Table 1.
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). The perfect 111 bp inverted terminal repeats (ITRs) at either end of the genome were identified in both strains. The entire HAdV-3 ITR sequences were very similar to the 108 bp ITR of the closely related HAdV-7 (strain Gomen) (Purkayastha et al., 2005) and the 114 bp ITR of HAdV-50 (strain Wan) (GenBank/EMBL accession no. AY737798
[GenBank]
), apart from seven mismatches in both cases. This contrasts with ITRs of the other HAdV-Bs: 136 bp for HAdV-3 (Tolun et al., 1979) and HAdV-7 (strain Greiner) (Shinagawa & Padmanabhan, 1980); 137 bp for HAdV-11 (Mei et al., 2003; Stone et al., 2003) and HAdV-35 (Kovács et al., 2004); and 121 bp for SAdV-21 (Davison et al., 2003). The ITRs did not contain the consensus motif CATCATCAAT found in most other HAdVs (Stone et al., 2003). Instead, they ended with the sequence CTATCTATAT, as found in HAdV-7. The conserved TATAATATACC motif that binds the complex of terminal protein precursor (pTP) and DNA polymerase during viral DNA replication was present at 8–18 bp (Temperley & Hay, 1992). The ITRs are critical to virus replication, as well as for gene activation and transcription. The transcription factor DNA-binding motifs, such as the NFIII/Oct-1 binding site at 40–50 bp, Sp1 binding site at 72–79 bp and NFI binding site at 26–39 bp, were also identified in the ITR regions of strains GZ1 and GZ2. Other inverted repetitive sequences were short and their function is not yet known. Inverted repetitive sequences are rife in HAdV-3 genomes and perhaps they act in the transcription stages. Moreover, inverted repeats were also identified in the genomes of most other HAdV-B (data not shown).
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). However, under detailed scrutiny, strain GZ2 had 93 mismatches and four gaps compared with strain GZ1, which caused typical CPE. The effect of mismatches is shown in Table 3. The substitutions in the strain GZ2 genome are obvious. Synonymous and non-synonymous substitutions resulting from mismatches are shown in Table 3. Eighteen proteins had synonymous substitutions and 27 proteins had non-synonymous substitutions, including a ‘C’ to ‘T’, which shortened the L2 pX protein (8.3 kDa in strain GZ1) to 7.6 kDa in GZ2 as a result of an internal stop codon (TAG) at nt 17459–17461. Of the 27 proteins with non-synonymous substitutions, high numbers were found in pTP (six substitutions) and hexon (five substitutions). Penton base, DNA Pol, 100 kDa and 12.1 kDa proteins also had three or four non-synonymous substitutions. The effects of such non-synonymous substitutions are not known. The synonymous substitutions may be single-nucleotide polymorphisms, as they did not change amino acids.
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).
E2
Three proteins required for viral DNA replication have been identified in the E2 transcriptional unit. Six non-synonymous substitutions were found in the E2B terminal protein precursor of strain GZ2, three in DNA polymerase protein and two in DNA-binding protein. The high number of substitutions in these proteins may potentially affect the replication course in the GZ2 genome.
E3
The E3 region of HAdVs encodes proteins that are not essential for in vitro growth. Both the 16.5 kDa and 15.3 kDa proteins were similar to adenoviral E3 proteins that are known to protect virus-infected cells against TNF-induced cytolysis (Horton et al., 1990). Non-synonymous substitutions occurred in half of the eight proteins in the E3 region, including the 15.3 kDa protein (‘R to Q’ and ‘R to C’).
E4
Unlike the other early transcripts, the proteins encoded by the E4 transcription unit have various functions, including viral RNA export and stabilization (Leppard, 1997). Six proteins were identified in both strains. Non-synonymous substitutions were found in three proteins of both strains.
IX and IVa2
Protein IVa2 in the intermediate gene region of HAdV-3 strain GZ2 had one non-synonymous substitution. Proteins IX and IVa2 play a critical role in controlling DNA packaging during AdV assembly (Zhang et al., 2001; Sargent et al., 2004) and act as transcriptional activators depending on the presence of the TATA box upstream for HAdV-3.
L1
Protein IIIa precursor and the 52/55K protein homologue (with a predicted molecular mass of 43.8 kDa) were identified in both strains. Three non-synonymous substitutions were found in protein pIIIa of strain GZ2. The 52/55 kDa protein acts as a scaffold for the capsid during virus assembly (Hasson et al., 1989).
L2
Four coding sequences were identified in the L2 regions, including the penton base protein III coding sequence. Penton base protein contains a conserved Arg–Gly–Asp (RGD) sequence and is involved in virus internalization through interaction with different host integrins (Wickham et al., 1993). The penton base proteins of strains GZ1 and GZ2 were 99.7 % identical at the nucleotide level and 99.5 % at the amino acid level. There were four non-synonymous substitutions in the penton base protein of strain GZ2. The effects of these mutations are difficult to predict, as the structural and functional domains of the penton base protein have yet to be determined. A non-synonymous substitution in the pX protein, which has a predicted molecular mass of 8.3 kDa in strain GZ1 and 7.6 kDa in strain GZ2, gave rise to an internal stop codon (TAG) at nt 17459–17461; the effects of this substitution are not yet known.
L3
Three coding sequences were found in the L3 regions: minor capsid protein precursor pVI, hexon and 23.7 kDa protease. The hexon protein accounted for 83 % of the adenovirus capsid and is known to be the principal antigenic component that results in protective immunity following natural infections. Leucine, asparagine and threonine are the three most abundant amino acids in the hexon of all HAdV-B (data not shown). A CLUSTAL-based multiple sequence alignment revealed seven HVRs (Fig. 3) between the hexons of HAdV-3, -5, -7, -11, -16, -21, -34 and -35, and SAdV-21, which account for 99 % of the serotype-specific variations (Crawford-Miksza & Schnurr, 1996). Most of the antibodies against the hexon in an adenovirus infection are directed against epitopes within these seven HVRs. A comparison of the hexon coding sequences from the strain GZ1 and GZ2 genomes identified two synonymous and five non-synonymous substitutions (Table 3
) and they were 99 % identical at the amino acid level. Interestingly, two synonymous substitutions in strain GZ2 occurred within the HVRs, whereas the five non-synonymous substitutions were found in the conserved regions of the hexon coding sequences. The seven HVRs contained >99 % of hexon serotype-specific residues. Both strains belonged to HAdV-3, so, in these regions, a complete identity between the two strains is not unexpected. On the other hand, the hexon epitopes are known to be conformational (Crawford-Miksza & Schnurr, 1996). Therefore, a change in a structural region, such as the M221V substitution in the conserved region of the L1 loop between HVR3 and HVR4, may affect protein folding in the antigenic regions to a certain extent.
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), selective activation of late viral protein synthesis (Hayes et al., 1990) and inhibition of granzyme B-mediated lysis (Andrade et al., 2001). Protein VIII is associated with the formation of a possible link between the hexon capsomere and core capsid components (Shenk, 2001). In the 100 kDa protein of strain GZ2, three synonymous and three non-synonymous substitutions were identified.
L5
The adenovirus fiber protrudes from the vertices of the capsid, is responsible for the virus binding to host cells and is a major determinant of tissue tropism. The fiber coding sequences of the two strains were 99 % identical at the amino acid level, with two non-synonymous substitutions. The substitutions resulted in the amino acid changes S10P and I286M, which occurred in the fiber ‘tail’ and ‘knob’, respectively. Unlike members of other HAdV groups, members of HAdV-B do not bind the CAR (Defer et al., 1990).
Conclusion
The complete genomes of HAdV-3 strains GZ1 and GZ2 have been sequenced and annotated. The difference in CPE caused by the two strains was analysed at the genome level. Based on bioinformatic analyses, non-synonymous substitutions in the E2 terminal protein precursor, DNA polymerase protein and DNA-binding protein of strain GZ2 were identified, which may potentially affect the replication course in the strain GZ2 genome. Two non-synonymous substitutions were also identified in the GZ2 E3 15.3 kDa protein, which is similar to the proteins that protect virus-infected cells against TNF-induced cytolysis. In the conserved regions of the hexon coding sequences, five non-synonymous substitutions were found. The differential CPEs induced by the two strains must be caused by the genome differences, although this has not yet been defined precisely. Both children infected with the adenovirus strains exhibited overt disease: the child infected with GZ1 had fever and bronchitis, whereas the child with GZ2 had pharyngeal conjunctivitis. Thus, although the viruses possessed different growth characteristics in vitro, they were both virulent. Finally, as it has a different tropism from CAR-interacting HAdVs, HAdV-3 has the potential to be developed as an alternative gene-transfer vector to HAdV-5.
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ACKNOWLEDGEMENTS |
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Received 9 September 2005;
accepted 8 February 2006.
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3' direction). Functionality embedded within the complementary strand and coding sequences transcribed from the complementary strand are indicated by ‘c’, e.g. (3925–3930)c. An asterisk indicates that the same position is found in strain GZ2 as in strain GZ1. – indicates that the strain does not include the correspondingprotein.
