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. 2002 Jan;76(1):421–426. doi: 10.1128/JVI.76.1.421-426.2002

Complete Nucleotide Sequence of the Rhesus Lymphocryptovirus: Genetic Validation for an Epstein-Barr Virus Animal Model

Pierre Rivailler 1, Hua Jiang 1, Young-gyu Cho 1, Carol Quink 1, Fred Wang 1,*
PMCID: PMC135707  PMID: 11739708

Abstract

We sequenced the rhesus lymphocryptovirus (LCV) genome in order to determine its genetic similarity to Epstein-Barr virus (EBV). The rhesus LCV encodes a repertoire identical to that of EBV, with 80 open reading frames, including cellular interleukin-10, bcl-2, and colony-stimulating factor 1 receptor homologues and an equivalent set of viral glycoproteins. The highly conserved rhesus LCV gene repertoire provides a unique animal model for the study of EBV pathogenesis.

Epstein-Barr virus (EBV)-related herpesviruses in the same gamma-1, or lymphocryptovirus (LCV), genera are known to naturally infect both Old and New World nonhuman primates, and the biology of these nonhuman LCVs appears indistinguishable from that of EBV (reviewed in reference 35). The potential utility of using Old World LCV as an animal model system was demonstrated by the ability to experimentally infect naive rhesus macaques with rhesus LCVs and reproduce many aspects of acute and persistent EBV infection in humans (20).

Previous studies revealed that Old World LCV genomes are organized in a colinear fashion with EBV and that EBV DNA cross-reacts with viral DNA from simian LCVs (11, 12). Rhesus LCV homologues for most of the EBV latent infection genes have been described (reviewed in reference 35). In virtually every aspect, these rhesus LCV latent infection genes are functionally interchangeable with the EBV genes despite modest degrees of homology (27 to 50% amino acid homology). However, the gene repertoire from the rhesus LCV, or any gamma-1 herpesvirus besides EBV, has not been completely characterized, particularly those genes encoding cellular homologues and viral glycoproteins that are highly relevant for studies in an animal model system. The development of a rhesus LCV genetic system to generate mutant viruses for use in experimental infections and study of molecular pathogenesis in vivo also requires a thorough understanding of the rhesus LCV genome and its sequence as a starting point.

Primary sequence and genome structure of rhesus LCV.

Six overlapping cosmid and two plasmid viral DNA clones were isolated from the rhesus LCV-infected B-cell line LCL8664 (Fig. 1A). A shotgun cloning and sequencing strategy was used to derive contiguous sequences from these eight viral DNA clones. The complete rhesus LCV sequence was assembled with a sevenfold average redundancy from 1,500 overlapping sequences of 300 to 800 nucleotides.

FIG. 1.

FIG. 1.

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Rhesus LCV genome, ORFs, and homology with EBV ORFs. (A) Overlapping cosmid and plasmid DNA clones used to sequence the rhesus LCV genome. Cosmids were identified from the library by hybridization with the EBV BamHI C (CC1, CD1), BamHI Q (QA15), BamHI L (LV28), BamHI D (DK12), and BamHI A (cos9) DNA fragments. RE1 and TR4 are EcoRI and BamHI fragments, respectively, cloned from Hirt DNA. The nucleotide coordinates for each viral DNA clone are as follows: CD1 (140 to 38,206), CC1 (1,785 to 39,553), QA15 (39,641 to 79,990), LV28 (70,760 to 111,969), DK12 (100,417 to 135,417), Cos9 (116,690 to 157,414), RE1 (156,359 to 166,542), and TR4 (166,175 to 783). An 88-bp gap between the CC1 and QA15 cosmid clones was deduced from four PCR clones amplified from rhesus LCV-infected cell DNA using primers from the CC1 and QA15 sequence. (B) Organization of the rhesus LCV genome. Homologues for the EBV lytic and latent origins of replication (ori-p; 7,511 to 9,357), ori-lyt DL (34,141 to 35,138), ori-lyt DR (138,080 to 139,080), major repeat regions IR1 (12,240 to 29,750), IR2 (33,674 to 34,047), IR3 (89,780 to 90,460), and IR4 (135,263 to 137,761), and terminal repeats (TR; 167,326 to 171,106) are identified in the rhesus LCV genome as shown. (C) Rhesus LCV ORFs and amino acid homology with EBV ORFs. The percent amino acid similarity is shown on the y axis. Latent, immediate-early, early, and late lytic ORFs are in black, dark grey, light grey, and white, respectively. Latent infection genes are identified by name (LMPs, EBERs, EBNAs [E], and BARF0 [A0]). Each lytic infection ORF is identified using the EBV nomenclature for BamHI ORFs. The orientations of the ORFs are shown by the direction of the arrow (i.e., right or left). The EBV BamHI fragment is indicated by the letter within the arrow, and the number of the ORF in the EBV BamHI fragment is given last, e.g., the rhesus LCV BCRF1 homologue is indicated by the rightward C1 arrow with approximately 85% amino acid similarity. (The ECRF4 ORF is the only exception to these abbreviations.) ORFs common to other herpesviruses are shown with a bold outline. The initiator codon for each ORF is positioned accurately, but the ORF size is not drawn to scale.

The rhesus LCV genome contains internal (IR1 to IR4) and terminal repeats (TR) as in EBV (Fig. 1B). The major internal repeat, IR1, contains 5.7 copies of a 3,072-bp motif that is 61.5% homologous to the 3,072-bp BamHI W fragment of the EBV IR1. The rhesus LCV TR consists of a 933-bp motif versus a 538-bp motif in the EBV TR, and there is no significant sequence homology besides a similarly high GC content (75%). Based on 5.7 copies in the major internal repeat and 4 TR copies, the rhesus LCV genome has 171,096 nucleotides (versus 172,231 bp in B95-8 EBV with 11.3 IR1 copies and 4 TR copies), with an overall GC content of 62% (60% for EBV), and 65% overall nucleotide homology with the EBV genome.

ORFs encoded in rhesus LCV.

Eighty open reading frames (ORFs) are identified in the rhesus LCV sequence (Fig. 1C, Table 1). Each of the rhesus LCV ORFs has a homologue in EBV, each is located in a similar relative position as in EBV, and every EBV ORF is represented in the rhesus LCV genome. Thus, the rhesus LCV, in contrast to the recently described New World primate marmoset LCV (5), has the same viral gene repertoire as EBV. The average homology among all EBV and rhesus LCV ORFs is 75.6% compared to an average homology of 47.3% between EBV and marmoset LCV ORFs (5). Because of the overall similarity in repertoire and sequence, we have adopted the EBV nomenclature with the prefix rh to identify the rhesus LCV ORFs.

TABLE 1.

Rhesus LCV genes and amino acid similarity with EBV ORFsa

Rhesus LCV
EBV
% aa similarity Description
Gene Exon Begins (nt) Stops (nt) Size (aa) Gene Length (aa)
LMP2A e2 138 354 71 LMP2A e2 71 66.2
LMP2A e3 437 535 33 LMP2A e3 33 51.2
LMP2A e4 644 892 83 LMP2A e4 83 67.5
LMP2A e5 974 1054 27 LMP2A e5 27 76.9
LMP2A e6 1134 1289 52 LMP2A e6 57 50.9
LMP2A e7 1377 1592 73 LMP2A e7 72 73.6
LMP2A e8 1673 1779 35 LMP2A e8 35 45.7
BNRF1 1836 5780 1,314 BNRF1 1,318 77.6 Tegument protein
LMP2A e9 5494 5930 LMP2A e9
EBER1 6653 6824 EBER1 Small RNA
EBER2 6967 7136 EBER2 Small RNA
BCRF1 9920 10453 177 BCRF1 170 84.1 IL-10 homologue
EBNA-LP 312 EBNA-LP 308 53.3 Nuclear protein
EBNA-LP C1 11765 11771 EBNA-LP C1
EBNA-LP C2 11930 11959 EBNA-LP C2
EBNA-LP W1 15018 15078 21 EBNA-LP W1 21 76.2
EBNA-LP W2 15160 15294 45 EBNA-LP W2 44 52.3
EBNA-LP Y1 29839 29871 11 EBNA-LP Y1 11 45.5
EBNA-LP Y2 29956 30060 34 EBNA-LP Y2 34 44.1
EBNA2 30612 32429 606 EBNA-2 490 29.8 Nuclear protein
BHLF1 33940 33089 283 BHLF1 660 63.6
BHRF1 35902 36477 190 BHRF1 191 72.8 be1-2 homologue
BFLF2 38519 37566 318 BFLF2 318 79.6
BFLF1 40106 38532 525 BFLF1 525 85.5 Glycoprotein
BFRF1 40465 41454 328 BFRF1 336 78.4 Tegument protein
BFRF2 41358 43169 603 BFRF2 591 80.4
BFRF3 43093 43605 169 BFRF3 176 69.2 Capsid protein
BPLF1 52963 43646 3,106 BPLF1 3,149 74.3 Tegument protein
BORF1 56698 57789 362 BORF1 364 86.5 DNA maturation
BOLF1 56699 53013 1,224 BOLF1 1,239 71.1 Tegument protein
BORF2 57852 60320 821 BORF2 826 87.5 Ribonucleotide reductase
BaRF1 60333 61241 300 BaRF1 302 96.0 Ribonucleotide reductase
BMRF1 61334 62548 404 BMRF1 404 85.9 DNA replication
BMRF2 62553 63626 357 BMRF2 357 86.0 Membrane protein
BMLF1 65658 64261 464 BMLF1 438 80.4 Transactivator
BSLF1 68479 65855 875 BSLF1 874 86.4 Helicase complex
BSRF1 68522 69187 218 BSRF1 218 89.4
BLLF3 70089 69250 276 BLLF3 278 87.3 dUTPase
BLRF1 70163 70451 102 BLRF1 102 74.5 Glycoprotein N, gp15
BLRF2 70542 71033 162 BLRF2 162 76.5
BLLF2 71609 71190 139 BLLF2 148 56.0
gp350 73401 71050 783 gp350 886 49.3 Glycoprotein, gp350
EBNA3A 955 EBNA3A 925 29.4 Nuclear protein
EBNA3A e1 73534 73845 117 EBNA3A e1 117 37.6
EBNA3A e2 73933 76446 838 EBNA3A e2 808 28.0
EBNA3B 928 EBNA3B 938 30.5 Nuclear protein
EBNA3B e1 76628 76993 122 EBNA3B e1 121 37.7
EBNA3B e2 77075 79495 806 EBNA3B e2 817 31.8
EBNA3C 1,157 EBNA3C 1,069 31.2 Nuclear protein
EBNA3C e1 79626 79970 117 EBNA3C e1 117 32.5
EBNA3C e2 80050 83184 1,040 EBNA3C e2 952 30.1
BZLF2 83897 83232 222 BZLF2 223 77.6 Glycoprotein, gp42
BZLF1 248 BZLF1 245 71.3 Transactivator
BZLF1 e3 84118 83997 41 BZLF1 e3 42 80.5
BZLF1 e2 84335 84227 36 BZLF1 e2 36 88.9
BZLF1 e1 85093 84581 171 BZLF1 e1 167 60.5
BRLF1 87109 85301 603 BRLF1 605 76.3 Transactivator
BRRF1 87108 88037 310 BRRF1 310 85.5
BRRF2 88226 89731 500 BRRF2 537 60.6
EBNA1 89767 91302 512 EBNA1 641 46.3 Episomal maintenance
BKRF2 91383 91796 136 BKRF2 137 81.6 Glycoprotein L, gp25
BKRF3 91778 92545 255 BKRF3 255 96.9 Uracyl DNA glucosidase
BKRF4 92556 93275 239 BKRF4 217 69.0
BBRF1 95691 97535 615 BBRF1 613 92.5 Capsid protein
BBLF4 95746 93317 810 BBLF4 809 93.4 Helicase complex
BBRF2 97438 98274 279 BBRF2 278 91.4
BBLF3 98846 98271 205 BBLF3 201 73.6 Helicase complex
BBLF2 100552 98945 514 BBLF2 522 72.8 Helicase complex
BBRF3 100652 101872 407 BBRF3 405 90.4 Glycoprotein M, gp84/113
BBLF1 102535 102311 75 BBLF1 75 72.0 Myristylated tegument protein
BGLF5 103902 102490 470 BGLF5 470 94.0 Alkaline exonuclease
BGLF4 105178 103889 452 BGLF4 455 89.6 Kinase
BDRF1 690 BDRF1 690 92.9 Packaging protein
BDRF1 e1 106502 107437 312 BGRF1 311 91.6
BGLF3 106503 105505 332 BGLF3 332 88.3
BGLF2 108437 107427 336 BGLF2 336 87.8
BGLF1 109911 108415 498 BGLF1 507 74.7
BDLF4 110597 109881 238 BDLF4 225 86.2
BDRF1 e2 110794 111930 378 BDRF1 379 94.7
BDLF3 112748 111969 260 BDLF3 234 46.6 Glycoprotein, gp150
BDLF2 114024 112813 403 BDLF2 420 68.5
BDLF1 114939 114034 302 BDLF1 301 96.7 Capsid protein
BcLF1 119097 114955 1,381 BcLF1 1,381 95.8 Capsid protein
BcRF1 119641 121374 578 BcRF1 575 83.0
BTRF1 121361 122572 425 BTRF1 425 86.6
BXLF2 124692 122569 708 BXLF2 706 85.1 Glycoprotein H, gp85
BXLF1 126517 124694 608 BXLF1 607 89.1 Thymidine kinase
BXRF1 126516 127265 250 BXRF1 248 80.6
BVRF1 127075 128781 566 BVRF1 570 84.6 Tegument protein
BVRF2 129594 131453 623 BVRF2 605 66.4 Capsid protein
BILF2 132248 131487 249 BILF2 248 75.0 Glycoprotein, gp78
LF3 137831 135159 905 LF3 924 42.7
LF2 146382 145093 429 LF2 429 92.5
LF1 147596 146343 417 LF1 422 75.3
BILF1 148684 147746 312 BILF1 312 80.4 Glycoprotein, gp64
ECRF4 151083 151946 289 ECRF4 289 79.3
BALF5 152230 149283 1,015 BALF5 1,015 94.8 DNA polymerase
BALF4 154927 152333 865 BALF4 857 85.6 Glycoprotein B, gp110
BARF0 156117 156602 165 BARF0 175 77.0 Nuclear protein
BALF3 156968 154914 684 BALF3 789 85.7 Transport protein
BALF2 160385 156984 1,134 BALF2 1,128 90.3 DNA binding protein
BALF1 161020 160472 183 BALF1 220 84.1 bcl-2 homologue
BARF1 161120 161782 220 BARF1 221 75.0 CSF1R homologue
LMP2A 495 LMP2A 498 57.0 Membrane protein
LMP2A e1 162521 162879 120 LMP2A 119 31.9
BNLF2B 163256 162960 94 BNLF2b 101 68.1
BNLF2A 163444 163265 60 BNLF2a 60 51.7
LMP1 e3 165723 164303 474 LMP1 e3 267 52.3
LMP1 e2 165894 165808 28 LMP1 e2 32 39.3
LMP1 e1 166242 165981 88 LMP1e1 88 30.7
LMP1 588 LMP1 386 32.4 Transforming gene
LMP2B e1 166602 166718 LMP2B e1
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a

Descriptions as defined for EBV ORFs. EBV ORFs derived by combining B95-8 sequence (2) (GenBank accession no. NC 001345) and Raji sequence (23) (GenBank accession no. M35547). Criteria used to evaluate rhesus LCV ORFs were as follows: >150 amino acids (aa), no more than 30% overlap with a known ORF. Shorter ORFs were identified only if homologues were identified in other herpesviruses. The complete rhesus LCV genome sequence has been deposited in GenBank (accession no. AY037858). Nucleotide homology between EBER-1 and rh EBER-1, 70.5%. Nucleotide homology between EBER-2 and rh EBER-2, 42.4%.

Rhesus LCV latent infection genes.

Homologues for the rhesus LCV EBV-encoded small RNAs (EBERs), EBNA-LP, two types of EBNA-2, EBNA-1, EBNA-3A, -3B, and -3C, LMP1, LMP2A, and LMP2B have been reported previously (3, 6, 8, 15, 24, 26, 27). The complete rhesus LCV sequence shows that there is also a homologue for the EBV BARF0 open reading frame, with 77% homology, suggesting that the family of EBV BamHI A transcripts expressed during latent infection are also likely to be conserved in the rhesus LCV. The latent infection genes are generally the least well conserved among all rhesus LCV genes (Fig. 1C, Table 1).

Conservation of LCV lytic infection genes.

Most of the EBV lytic infection genes have homologues in other herpesviruses due to the conserved mechanisms for herpesvirus replication. These 56 ORFs (24 late, 32 early, and 1 immediate-early lytic infection viral gene product) have an average homology of 82.8% with the rhesus LCV homologues (Fig. 1C, ORFs with bold outline). Fifteen EBV lytic infection ORFs do not have homologues in other herpesviruses, i.e., they are restricted to gamma-1 herpesviruses, and the rhesus LCV homologues for these ORFs have an average homology of 60.3%. These genes have presumably evolved more recently and are generally less well conserved between EBV and rhesus LCV.

ORFs encoding homologues of cellular proteins.

Four EBV lytic infection genes are cell gene homologues likely to have been captured because they provide a biologic advantage during EBV infection. These include a viral interleukin-10 (vIL-10; BCRF1), two bcl-2 homologues (BHRF1 and BALF1), and a colony-stimulating factor 1 receptor (CSF-1R) homologue (BARF1) (14, 18, 19, 32). These viral genes are not essential for EBV-induced transformation of B-cell growth and for EBV replication in vitro (7, 18, 33). Rhesus LCV has captured an identical repertoire of cellular homologues. Conservation of these ORFs in the rhesus LCV (73 to 84% homology relative to the EBV proteins) indicates that these cellular homologues provide biologic advantages that are common to both EBV and rhesus LCV infection in their natural hosts.

Viral membrane proteins.

Viral membrane proteins are important for cell tropism, as targets for the host immune response, and for pathogenesis of infection in vivo. All 10 EBV ORFs known to encode viral membrane glycoproteins are positionally conserved in the rhesus LCV. Five of these glycoproteins are conserved in all herpesviruses (gB, gH, gL, gM, and gN) and are important for herpesvirus virus assembly, egress, and cell fusion (13, 16, 17, 21). These glycoproteins are well conserved in the rhesus LCV (74 to 90% homology with the EBV glycoproteins). Five glycoproteins are restricted to gammaherpesviruses, and these viral gene products are likely to be important for LCV biology and pathogenesis. Among these, gp350 and gp150 have the lowest degree of homology between EBV and the rhesus LCV, 49.3 and 46.6% homology, respectively. gp350 is the major viral membrane glycoprotein that binds to CR2/CD21 and is a major determinant for EBV’s B-cell tropism (22, 34). gp150 is not essential for EBV replication and infection in vitro (4), suggesting an important role for this glycoprotein during human and rhesus LCV infection in vivo.

The rhesus LCV is only the second completely sequenced genome from the oncogenic LCV genera. The EBV B95-8 strain was the first gamma-1 herpesvirus fully sequenced (2). Portions of several other EBV strains have been sequenced (23, 29). Analysis of an 11-kb DNA sequence from Raji EBV demonstrated that the B95-8 strain is a deletion mutant, missing a duplicated ori-lyt sequence (DR) at the right-hand side of the genome (10, 23, 25). Thus, the rhesus LCV genome is the first complete sequence derived from a prototypical LCV genome.

The identical repertoire of lytic and latent infection genes between EBV and the rhesus LCV demonstrates the close genetic relationship between these two viruses and provides genetic validation that the rhesus LCV is an accurate model for studying EBV pathogenesis. The conservation of a type 1 latency EBNA-1 promoter (28) and the existence of two different rhesus LCV types similar to type 1 and 2 EBV (6) provide further evidence of the biologic and genetic similarities between EBV and the rhesus LCV. Thus, Old World LCVs, such as the rhesus LCV, appear to have evolved very closely in parallel with EBV, whereas New World LCVs, such as the marmoset LCV, appear to have evolved somewhat differently despite the overt biologic similarities (5). Thus, the evolutionary distances between human, Old World, and New World LCVs are similar to the relationships between New World, Old World, and human hosts. Studies in both New and Old World model systems may provide a better understanding of how various viral genes contribute to successful EBV infection and pathogenesis in vivo.

Primates have been touted as important animal model systems for studying human virus infection because of the strong similarities in both the viruses and the natural hosts. To our knowledge, only two other herpesviruses naturally infecting Old World nonhuman primate species have been completely sequenced, rhesus rhadinovirus (RRV) and simian varicella virus (SVV) (1, 9, 30), and both have been proposed as animal models for human herpesvirus infections (31, 36). However, the viral gene repertoire from these two viruses is not identical to their human counterparts, Kaposi’s sarcoma herpesvirus (KSHV) and varicella-zoster virus (VZV). RRV does not encode homologues for the KSHV K3, K5, K7, K8, K8.1, and K12 ORFs (1, 30). In addition, the dihydrofolate reductase (DHFR) homologue is encoded in a different location and the copy numbers of macrophage inflammatory protein and viral interferon regulatory factor homologues are different.

Similarly, the SVV and VZV genomes do not have an identical gene repertoire. SVV does not encode a homologue for the VZV ORF2, a gene with unknown function, and SVV encodes for a novel ORF A that is a truncated form of VZV ORF4 (9). In addition, the average homology of RRV and SVV ORFs with their human herpesvirus counterparts is relatively low, approximately 55%, versus 75% between rhesus LCV and EBV. Thus, the identical gene repertoire and high overall sequence homology make the rhesus LCV a uniquely accurate animal model for studying EBV pathogenesis.

Acknowledgments

We acknowledge members of the Massachusetts General Hospital DNA Sequencing Core (Harry Orf, Brian Seed, Dan Stetson, and David Levin) and the Brigham & Women’s Hospital Genetics Core (David Beier) for assistance with and performance of high-throughput DNA sequencing. We thank Elliott Kieff for valuable advice.

This work was supported by grants from the U.S. Public Health Service (CA68051) and the American Heart Association.

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