Open Access

Analysis of the nucleotide sequence of the guinea pig cytomegalovirus (GPCMV) genome

  • Mark R Schleiss1Email author,
  • Alistair McGregor1,
  • K Yeon Choi1,
  • Shailesh V Date2,
  • Xiaohong Cui3 and
  • Michael A McVoy3
Virology Journal20085:139

DOI: 10.1186/1743-422X-5-139

Received: 15 October 2008

Accepted: 12 November 2008

Published: 12 November 2008

Abstract

In this report we describe the genomic sequence of guinea pig cytomegalovirus (GPCMV) assembled from a tissue culture-derived bacterial artificial chromosome clone, plasmid clones of viral restriction fragments, and direct PCR sequencing of viral DNA. The GPCMV genome is 232,678 bp, excluding the terminal repeats, and has a GC content of 55%. A total of 105 open reading frames (ORFs) of > 100 amino acids with sequence and/or positional homology to other CMV ORFs were annotated. Positional and sequence homologs of human cytomegalovirus open reading frames UL23 through UL122 were identified. Homology with other cytomegaloviruses was most prominent in the central ~60% of the genome, with divergence of sequence and lack of conserved homologs at the respective genomic termini. Of interest, the GPCMV genome was found in many cases to bear stronger phylogenetic similarity to primate CMVs than to rodent CMVs. The sequence of GPCMV should facilitate vaccine and pathogenesis studies in this model of congenital CMV infection.

Findings

Guinea pig cytomegalovirus (GPCMV) serves as a useful model of congenital infection, due to the ability of the virus to cross the placenta and infect the fetus in utero [13]. This model is well-suited to vaccine studies for prevention of congenital cytomegalovirus (CMV) infection, a major public health problem and a high-priority area for new vaccine development [4]. However, an impediment to studies in this model has been the lack of detailed DNA sequence data. Although a number of reports have identified specific gene products or clusters of genes [511], to date a full genomic sequence has not been available.

We recently reported the construction and preliminary sequence map of a GPCMV bacterial artificial chromosome (BAC) clone maintained in E. coli [12, 13], and this clone was used as an initial template for sequence analysis of the full GPCMV genome. BAC DNA was purified using Clontech's NucleoBond® Plasmid Kits as described previously [14] and both strands were sequenced using an ABI PRISM® 377 DNA Sequencer, with primers synthesized, as needed, to 'primer-walk' the nucleotide sequence. In parallel, Hin d III- and EcoR I-digested fragments were gel-purified and cloned into pUC and pBR322-based vectors as previously described [15]. Plasmid sequences were determined from overlapping Hin d III and EcoR I fragments using the map coordinates originally described by Gao and Isom [16]. These sequences were compared to the BAC sequence to facilitate assembly of a full-length contiguous sequence. Since the cloning of the BAC in E. coli involved insertion of BAC origin sequences into the Hin d III "N" region of the viral genome, sequence obtained from this specific restriction fragment cloned in pBR322 was utilized for assembly of the final contiguous sequence; analysis of this sequence confirmed that there were no adventitious deletions in the Hin d III "N" region generated during the original BAC cloning process. Since a deletion in the Hin d III "D" region occurred during cloning of the GPCMV BAC in E. coli [17], DNA sequence from a plasmid containing the full-length Hin d III "D" fragment was similarly obtained, and used for assembly of the final contiguous sequence. The GPCMV genomic sequence has been deposited with GenBank (Accession Number FJ355434).

Sequence analysis of GPCMV revealed a genome length of 232,678 bp with a GC content of 55%. This value is in agreement with the value of 54.1% determined previously by CsCl buoyant density centrifugation [18]. A total of 326 open reading frames (ORFs) were identified that were capable of encoding proteins of ≥ 100 amino acids (aa). For ORFs predicted by the sequence analysis that had substantial overlap with other adjacent or complementary GPCMV ORFs that appeared to encode gene products that were highly conserved in other cytomegaloviruses, only those sequences with < 60% overlap with these highly conserved ORFs were further analyzed. ORFs homologous to those encoded by other CMVs with an e-value of < 0.1 and ≥ 100 aa were identified, based on comparisons analyzed using NCBI Blast (blastall version program 2.2.16). Of the ORFs so identified, 104 had sequence and/or positional homology to one or more ORFs encoded by human (HCMV), murine (MCMV), rat (RCMV), rhesus (RhCMV), chimpanzee (CCMV), or tupaia herpesvirus (THV) cytomegaloviruses (Table 1). Of note, homologs of HCMV ORFs UL23 through UL122 were identified [19]. For ease of nomenclature, we have designated these ORFs using upper case font (GP23 through GP122). ORFs with homologs in other CMVs that do not correspond to HCMV UL23 through UL122 have been designated with a lower case "gp" prefix. Homologs of HCMV UL41a (69 aa; gp38.2), UL51 (99 aa; GP51), and UL91 (87 aa; GP91) were annotated in these initial analyses, based primarily on positional, and not sequence, homology to the respective HCMV ORFs. Three ORFs, homologs of MHC class I genes known to be encoded by multiple other CMVs (gp 147–149, Table 1) were also identified. One ORF, gp1 (homolog of CC chemokines), did not have a positional or sequence homolog when compared to other CMVs, but was included in the annotation because of its previous molecular characterization [9]. Including ORFs with mapped exons, the total number of ORFs annotated in this preliminary analysis was 105 [Table 1].
Table 1

GPCMV Open Reading Frames (ORFs)

ORF

Strand

Position

Size (aa)

Protein Characteristics and Cytomegalovirus Homologs

  

From

To

  

gp1

C

12701

13006

101

GPCMV MIP 1-alpha; homology to multiple CC chemokines

gp2

 

15098

15949

283

Homology to MCMV M69a

gp3

C

17461

19827

788

Homology to THV T5b; US22 superfamily

gp4

C

21093

21416

107

Homology to RCMV r136d

gp5

C

26985

28097

370

Homology to MCMV m32a

gp6

 

30089

30454

121

Homology to MCMV glycoprotein family m02a

gp7

C

32003

32308

101

Homology to RhCMV rh42c

GP23

C

33561

34763

400

UL23 homolog; US22 gene superfamily

GP24

C

35000

36217

405

UL24 homolog; US22 superfamily

gp24.1

 

36802

37224

140

Homology to MCMV M34 proteina

GP25

 

37187

38455

422

UL25 homolog; tegument protein

GP26

C

38621

39058

145

UL26 homolog

GP27

C

39508

41472

654

UL27 homolog

GP28

C

41572

42639

355

UL28 homolog; US22 superfamily

GP28.1

C

43344

44546

400

UL28 homolog; US22 superfamily

GP28.2

C

44912

46099

395

UL28 homolog; US22 superfamily

GP29

C

46211

46882

223

UL29 homolog; US22 superfamily

gp29.1

C

47579

48034

151

Homology to RCMV R36 proteind; potential homolog of viral cell death suppressor

GP30

C

49363

51060

565

UL30 homolog

GP31

 

51354

52832

492

UL31 homolog

GP32

C

53073

54626

518

UL32 homolog

GP33

 

54846

56129

427

UL33 homolog; 7-TMR GPCR superfamily

GP34

 

56482

58065

527

UL34 homolog

GP35

 

58269

59927

552

UL35 homolog

GP37

C

60047

60964

305

UL37 homolog

GP38

C

61321

62385

354

UL38 homolog

gp38.1

C

62960

63817

436

Positional homolog of HCMV UL40

gp38.2

C

63876

65186

69

Positional homolog of HCMV UL41a

gp38.3

C

65881

66735

284

Positional homolog of HCMV UL42

gp38.4

C

67254

67619

121

Homology to RCMV r42d

GP43

C

68208

69221

337

UL43 homolog

GP44

C

69209

70432

407

UL44 homolog

GP45

C

71144

73933

929

UL45 homolog

GP46

C

74036

74833

265

UL46 homolog

GP47

 

75441

77846

801

UL47 homolog

GP48

 

78051

84332

2093

UL48 homolog

GP49

C

84746

86386

546

UL49 homolog

GP50

C

86362

87426

354

UL50 homolog

GP51

C

87551

87850

99

UL51 homolog; terminase subunit

GP52

 

88170

89750

526

UL52 homolog

GP53

 

89743

90729

328

UL53 homolog

GP54

C

90821

94174

1117

UL54 homolog; DNA polymerase

GP55

C

94216

96921

901

UL55 homolog; glycoprotein B

GP56

C

96818

99085

755

UL56 homolog; terminase subunit

GP57

C

99236

102919

1227

UL57 homolog

gp57.1

C

104872

105258

128

Homology to RCMV r23.1d

gp57.2

 

107338

107712

124

Homology to RCMV R53d

GP69

C

108547

111678

1043

UL69 homolog

GP70

C

112387

115590

1067

UL70 homolog; helicase-primase

GP71

 

115589

116365

258

UL71 homolog

GP72

C

116528

117601

357

UL72 homolog; dUTPase

GP73

 

117683

118084

133

UL73 homolog; glycoprotein N

GP74

C

118031

119143

370

UL74 homolog; glycoprotein O

GP75

C

119595

121766

723

UL75 homolog; glycoprotein H

GP76

 

121931

122770

279

UL76 homolog

GP77

 

122484

124343

619

UL77 homolog

GP78

 

124725

125969

414

UL78 homolog; 7-TMR GPCR superfamily

GP79

C

126164

127111

315

UL79 homolog

GP80

 

126972

129281

769

UL80 homolog; CMV protease

GP82

C

129576

131141

521

UL82 homolog; pp71

GP83

C

131361

133058

565

UL83 homolog; pp65

GP84

C

133286

134737

483

UL84 homolog

gp84.1

 

134994

135476

160

Homolog of RhCMV rh116e

GP85

C

135035

135946

303

UL85 homolog

GP86

C

136227

140276

1349

UL86 homolog

GP87

 

140657

143578

973

UL87 homolog

GP88

 

143481

144752

423

UL88 homolog

GP89ex2

C

144798

145928

376

UL89 homolog; terminase subunit, exon 2

GP91

 

146356

146619

87

UL91 homolog

GP92

 

146616

147245

209

UL92 homolog

GP93

 

147456

148985

509

UL93 homolog

GP94

 

149118

149873

251

UL94 homolog

GP89ex1

C

150285

151166

291

UL89 homolog; terminase subunit, exon 1

GP95

 

151284

152489

401

UL95 homolog

GP96

 

152722

153084

120

UL96 homolog

GP97

 

153164

154981

605

UL97 homolog; protein kinase

GP98

 

155001

156788

595

UL98 homolog; alkaline nuclease

GP99

 

156701

157222

173

UL99 homolog; pp28

gp99.1

 

157406

158020

204

Homology to RCMV r4d

GP100

C

157529

158578

349

UL100 homolog; glycoprotein M

GP102

 

158908

161193

761

UL102 homolog

GP103

C

161307

162104

265

UL103 homolog

GP104

C

162067

164160

697

UL104 homolog; portal

GP105

 

164000

166783

927

UL105 homolog; helicase-primase

gp105.1

 

176502

176894

130

Homology to RhCMV rh55c

GP112ex1

 

177066

177839

258

UL112 homolog; replication accessory protein, exon 1

GP112ex2

 

178403

179257

284

UL112/UL113 homolog; replication accessory protein, exon 2

GP114

C

179168

180259

363

UL114 homolog; uracil glycosylase

GP115

C

180325

181101

258

UL115 homolog; glycoprotein L

GP116

C

181146

181994

282

Homology to THV t116b; possible functional homolog of UL119; Fc receptor/immunoglobulin binding domains

GP117

C

182202

182777

191

UL117 homolog

GP119.1

C

185103

185591

162

UL119 homolog; homology to MCMV M119.1a

GP121

C

186635

187681

348

UL121 homolog; homology to THV t121.4b

GP122

C

188292

189260

322

UL122 homolog; HCMV IE2; immediate early transactivator

gp123

 

195838

196893

351

MCMV IE2 homologa; US22 superfamily

gp138

C

201275

202750

491

Homology to RCMV r138d

gp139

C

204624

206717

697

Homology to THV T5b; US22 superfamily

gp140

 

206446

206853

135

Homology to CCMV UL132g

gp141

C

206977

208584

535

Homology to HCMV US23h; US22 superfamily

gp142

C

208852

210546

564

Homology to HCMV US24h; US22 superfamily

gp143

C

210799

212532

577

Homology to THV T5b; US22 superfamily

gp144

C

213034

215328

764

Homology to US26h; US22 gene superfamily

gp145

C

215601

217499

632

Homology to HCMV IRS1/TRS1h; US22 superfamily

gp146

C

218106

219839

577

Homology to HCMV IRS1/TRS1h; US22 superfamily

gp147

C

223464

225026

520

MHC class I homolog

gp148

C

225938

227389

483

MHC class I homolog

gp149

C

228845

230728

627

MHC class I homolog

a Genbank NC_004065.1

b Genbank NC_004065.1

c Genbank NC_006150.1

d Genbank AF232689.2

e Genbank YP_068209.1

f Genbank AY486477.1

g Genbank NC_003521.1

h Genbank NC_001347

A map of the GPCMV genome illustrating the relative positions of these ORFs is shown in Fig. 1. ORFs that represent homologs of the individual exons of spliced HCMV genes, in particular UL89 (terminase) and UL112/UL113 (replication accessory protein) are annotated separately. The splice junction for the GP89 mRNA was predicted based on comparisons to other CMVs. For the UL112/113 region, further studies will be required to map the precise splicing patterns of the putative transcripts encoded by this region of the GPCMV genome. Similarly, the ORF encoding the sequence homolog of the HCMV IE transactivator, UL122, has been annotated without regard to the splicing events previously shown to take place in this region of the genome [20]; further analyses of cDNA from this and other GPCMV genome regions of IE transcription, including those encoded in the Hin d III 'D' region of the genome, will likely result in annotation of multiple heretofore unidentified ORFs. A comprehensive table of all ORFs > 25 aa and their homology to other CMV genomes is provided in additional files 1 and 2. As RNA analyses are completed, the total number of annotated GPCMV ORFs will expand in number.
Figure 1

Protein Coding Map of GPCMV Genome. Schematic representation of the GPCMV genome demonstrating ORFs described in the text. GPCMV ORFs with positional and/or sequence homology to HCMV ORFs are indicated in bold with upper case prefixes (GP23 through GP122). ORFs that lack sequence or positional homologs in HCMV but share homology with ORFs in other CMVs are indicated with lower case prefixes (see Table 1). Only the 5' terminal repeat (TR) is shown; however, in about 50% of genomes the TR is duplicated at the 3' end [18]. Color-coding indicates ORFs of interest for vaccine and pathogenesis studies: blue, envelope glycoprotein homologs; green, putative immune evasion/immune modulation gene homologs; red, US22 superfamily homologs.

The schematic representation of GPCMV ORFs demonstrated in Fig. 1 highlights several gene families of particular interest. Of particular interest and importance to vaccine studies in the guinea pig model are conserved homologs of the ORFs encoding major envelope glycoproteins gB, gH/gL/gO/, and gM/gN. These glycoproteins are important determinants of humoral immune responses in the setting of CMV infection, and serve as potential subunit vaccine candidates. Of these, the gB homolog has been demonstrated to confer protection against congenital GPCMV infection in subunit vaccine studies [2123]. Homologs of putative HCMV immune modulation genes, including G-protein coupled receptors and major histocompatibility class I homologs, were also identified [24]. Also of interest was the presence of multiple US22 gene family homologs, heavily clustered near the rightward terminus of the GPCMV genome. These ORFs predict protein products that are analogous to the MCMV dsRNA-binding proteins, M142 and M143, that have been shown to inhibit dsRNA-activated antiviral pathways [25, 26]. Members of this family have also been implicated in macrophage tropism in MCMV [27]. Our sequence analysis also confirmed the findings of Liu and Biegalke [8] that the GPCMV genome does not encode a positional homolog of the antiapoptotic HCMV UL36 gene [28]. However, an ORF with homology to R36, which encodes the presumed RCMV cell death suppressor, was identified (gp29.1, Table 1). Further studies will be required to determine whether this putative gene supplies a UL36-like function.

It was also of interest to note the presence of ORFs that have apparent homology to the MCMV M129-133 region. This region has positional homologs in human and primate CMVs [2931], but is absent in THV [32]. Recently, it was determined that passage of GPCMV in cultured fibroblasts promotes the deletion of a ~1.6-kb locus containing potential positional homologs of this gene cluster. The presence of this 1.6 kb locus was found by Inoue and colleagues to be associated with an enhanced pathogenesis of GPCMV in vivo [33]. We independently confirmed the presence of this locus and its sequence in our salivary gland-derived viral stocks, and have included this sequence in our GenBank annotation (Accession Number FJ355434). Further studies will be required to fully annotate the transcripts encoded by this region of the GPCMV genome. Interestingly, the original GPCMV BAC clone that we sequenced was derived using GPCMV viral DNA obtained after long-term tissue culture passage of ATCC 2122 viral stock, and not surprisingly this BAC was found to lack the 1.6 kb virulence locus [12]. Subsequently, PCR and preliminary sequencing of a more recently obtained GPCMV BAC clone with an excisable origin of replication [17] revealed that the 1.6-kb sequence was retained in this clone. The apparent modifications of this locus that occur following viral passage on fibroblast cells are reminiscent of the mutations and deletions that occurred during fibroblast-passage of HCMV [34] and rhesus CMV [35]. The congruence of these events suggests that the selective pressures that promote mutational inactivation of genes in this region may be similar across viral species. Additional analyses, including sequencing of a full-length GPCMV genome derived from replicating virus in vivo, will be required to determine what other deletions or mutations are present in genomes from tissue culture-passaged viruses. Since additional ORFs are likely to be identified by these analyses, we have annotated the first ORF identified in the BAC sequence to the right of this 1.6 kb region as gp138 (Fig. 1), to allow for ease of nomenclature as ORFs in this virulence locus are better characterized. Application of other genome sequence analysis methods, including identification of small or overlapping genes and further assessment of mRNA splicing or unconventional translation signals, will likely result in identification of other putative ORFs in future studies [36].

Comparisons of GPCMV ORFs with sequences from other CMV genomes yielded interesting results. ORF translations were compared with all proteins from the 6 sequenced CMV genomes (HCMV, MCMV, RCMV, RhCMV, THV, and CCMV), and hits with e-values less than 1e-5 were aligned individually for each protein, using both ClustalW (version 1.82; [37]) and Muscle (version 3.6; [38]). The alignments were then used to generate trees based on neighbor-joining using JalView. Clustal trees for glycoproteins B (GP55) and N (GP73) are shown in Fig. 2, with distance scores indicated. Overall, comparison of the various glycoproteins (gB, gM, gH, and gO) yielded similar phylogenies, with GPCMV glycoproteins generally appearing closer to primate CMVs than rodent CMVs [39], except for the gN homolog, which appears closer to rodents. ClustalW and Muscle comparisons of GPCMV ORFs with homologous ORFs from the other sequenced CMVs are provided in additional file 3.
Figure 2

Comparison of GPCMV Glycoproteins with CMV Homologs. Sequences of GPCMV glycoproteins were aligned with glycoproteins from six other CMV genomes (HCMV, MCMV, RCMV, RhCMV, THV, and CCMV) using both ClustalW [37] and Muscle [38] using default parameters. Phylogenetic trees (neighbor joining) were generated from these alignments using Jalview. Numbers at each node indicate mismatch percentages. Interestingly, GPCMV sequences closely match THV sequences (see also, supplementary information), and generally appear closer to primate CMV glycoproteins in pair-wise comparisons than to rodent CMV glycoproteins, as previously observed for gB [39]. Clustal comparisons for conserved glycoproteins gB (GP55; Panel A) and gN (GP73; Panel B) are indicated.

In summary, the complete DNA sequence of GPCMV was determined, using a combination of sequencing of BAC DNA, viral DNA, and cloned Hin d III and Eco RI fragments. These analyses identified both conserved ORFs found in all mammalian CMVs, as well as the presence of novel genes apparently unique to the GPCMV. These similarities underscore the usefulness of the guinea pig model, with positive translational implications for development and testing of CMV intervention strategies in humans. Further characterization of the GPCMV genome should facilitate ongoing vaccine and pathogenesis studies in this uniquely useful small animal model of congenital CMV infection.

Declarations

Acknowledgements

Grant support was provided from NIH HD044864-01 and HD38416-01 (to MRS) and R01AI46668 (to MAM). The authors acknowledge helpful discussions and input from Becket Feierbach (Genentech, Inc.). The authors also acknowledge the technical contributions of Yonggen Song and the gift of the Hin d III "D" plasmid from HC Isom, Penn State University.

Authors’ Affiliations

(1)
Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota
(2)
Genentech Inc.
(3)
Division of Infectious Diseases, Department of Pediatrics, Virginia Commonwealth University School of Medicine

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© Schleiss et al; licensee BioMed Central Ltd. 2008

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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