J Virol 77(12): 6620-6636

Complete Sequence and Genomic Analysis of Rhesus Cytomegalovirus

Vaccine and Gene Therapy Institute, Oregon Health & Science University,^{Division of Pathobiology and Immunology, Oregon National Primate Research Center, Beaverton, Oregon 97006,}^{The David Axelrod Institute, Wadsworth Center, Albany, New York 12201,}^{Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon 97239}⁴

^{Corresponding author. Mailing address for David G. Anders: The David Axelrod Institute, Wadsworth Center for Molecular Genetics, Albany, NY 12201-2002. Phone: (518) 474-8969. Fax: (518) 474-3181. E-mail:}gro.htrowsdaw@sredna. Scott W. Wong, Vaccine and Gene Therapy Institute, OHSU, West Campus, 505 NW 185th Avenue, Beaverton, OR 97006. Phone: (503) 690-5285. Fax: (503) 418-2719. E-mail: ude.usho@sgnow.

Received 2002 Nov 21; Accepted 2003 Mar 19.

Abstract

The complete DNA sequence of rhesus cytomegalovirus (RhCMV) strain 68-1 was determined with the whole-genome shotgun approach on virion DNA. The RhCMV genome is 221,459 bp in length and possesses a 49% G+C base composition. The genome contains 230 potential open reading frames (ORFs) of 100 or more codons that are arranged colinearly with counterparts of previously sequenced betaherpesviruses such as human cytomegalovirus (HCMV). Of the 230 RhCMV ORFs, 138 (60%) are homologous to known HCMV proteins. The conserved ORFs include the structural, replicative, and transcriptional regulatory proteins, immune evasion elements, G protein-coupled receptors, and immunoglobulin homologues. Interestingly, the RhCMV genome also contains sequences with homology to cyclooxygenase-2, an enzyme associated with inflammatory processes. Closer examination identified a series of candidate exons with the capacity to encode a full-length cyclooxygenase-2 protein. Counterparts of cyclooxygenase-2 have not been found in other sequenced herpesviruses. The availability of the complete RhCMV sequence along with the ability to grow RhCMV in vitro will facilitate the construction of recombinant viral strains for identifying viral determinants of CMV pathogenicity in the experimentally infected rhesus macaque and to the development of CMV as a vaccine vector.

Abstract

Cytomegaloviruses are the prototypic members of the betaherpesvirus subgroup. Like all herpesviruses, they share several characteristics with other viruses of the family, including virion structure and the ability to establish persistent and latent infections. What makes the betaherpesvirus subgroup unique among the herpesviruses is their tropism for the salivary gland, their species specificity, and their slow growth in culture systems (25). Weller et al. coined the term cytomegalovirus to reflect the cytopathic effect caused by virus infection and the virus's role in genitally acquired cytomegalic inclusion disease (75).

Human cytomegalovirus (HCMV) infection is generally asymptomatic in immunocompetent hosts. Typically, HCMV is acquired subclinically during childhood and persists throughout the individual's life. Persistence is characterized by the presence of latent viral genomes that periodically reactivate to produce infectious virus that can be shed intermittently in saliva, urine, semen, cervical secretions, and breast milk (25). Data suggest that persistence is established not only by the virus's ability to infect various cell types within the host, but also by the virus's ability to differentially regulate gene expression and by virally encoded immunomodulators (23, 30, 32, 43, 44, 57, 60, 64). When primary HCMV infection is acquired during adulthood, the virus is capable of doing considerably more damage. In particular, primary infections during pregnancy can lead to congenital abnormalities in the fetus and morbidity and mortality in immunocompromised individuals, including transplant patients and persons with AIDS.

Thus, with advances in medical procedures such as organ allografting and immunosuppressive posttransplant therapies as well as with increasing numbers of people infected with the human immunodeficiency virus (HIV), HCMV is proving to be a significant pathogen. Currently, the only Food and Drug Administration-approved antiviral therapies include the drugs ganciclovir, foscarnet, and cidofovir, each of which targets the viral DNA polymerase, and Vitravene, a novel antisense compound used to treat CMV retinitis (38). Although helpful, these drugs have numerous drawbacks, which include limited efficacy and toxic side effects and frequent emergence of resistant viral isolates during long-term therapy (17, 19, 72).

Despite the growing information on HCMV gene products and pathogenesis, there is a limitation on the ability to develop effective treatments for primary HCMV infection or reactivation of latent infection. To address these limitations, four animal models are being evaluated for antiviral treatments against HCMV and for overall cytomegalovirus pathogenesis. These models are guinea pig cytomegalovirus, murine cytomegalovirus (MCMV), rat cytomegalovirus (RCMV), and more recently, rhesus cytomegalovirus (RhCMV). The guinea pig cytomegalovirus model is well suited for congenital cytomegalovirus infection because the virus can cross the placenta and produce infection in utero (31). Despite this advantage, the guinea pig cytomegalovirus model is not well suited to the analysis of drug therapy, as the virus is resistant to ganciclovir therapy (50). The genomes of MCMV and RCMV have been completely sequenced, and these models are providing valuable information on both cytomegalovirus pathogenicity and antiviral therapies (59, 73). However, MCMV and RCMV are evolutionarily far removed from HCMV, and the results obtained in these systems may not be applicable to treatment and prevention of HCMV infection (51, 61).

Over the past decade, researchers have been working to develop an RhCMV model to study HCMV pathogenesis and antiviral therapies (2, 3, 7, 8, 48, 49, 70, 74). RhCMV was first recognized 70 years ago as an incidental infection of rhesus macaques (15, 16). Several nonhuman primate cytomegaloviruses have been isolated since that time, each of which is different from HCMV in host range and DNA content (3, 18, 63, 69). RhCMV is ubiquitous in captive rhesus macaques, with infection rates of greater than 90% by the first year of life (39, 41, 74). Cytomegalovirus infections in macaques share several features with HCMV infections. The majority of RhCMV infections are subclinical, and healthy adults tend to shed virus in their urine, saliva, semen, cervical secretions, and breast milk for years. Experimental congenital central nervous system disease has been produced in rhesus macaques by inoculating fetuses in utero intracerebrally or intra-amniotically (49).

Like humans infected by HIV, rhesus macaques are susceptible to infection with simian immunodeficiency virus (SIV). Studies utilizing SIV-infected rhesus macaques have demonstrated that disseminated cytomegalovirus disease is quite similar to that observed in HIV-infected humans (8). These symptoms can include orchitis, encephalitis, and respiratory tract disease. In addition, cytomegalovirus infections have been seen in the bone marrow and lungs of rhesus macaques that have been immunosuppressed with antithymocyte globulin, cyclophosphamide, and cortisone and subsequently inoculated with varicella-zoster virus, which is similar to what has been observed in people who acquire HCMV infection after transplant surgery (53). Lastly, studies of the host immune response to RhCMV appear to parallel HCMV infection, as cytomegalovirus-specific cytotoxic T lymphocytes are essential in controlling infection (40).

Studies of a nonhuman primate cytomegalovirus such as RhCMV are relevant to the study of HCMV, as this virus is evolutionarily closer to humans than the rodent cytomegalovirus isolates (51). Until now, only a limited number of reports have demonstrated the similarity of HCMV and RhCMV at the genomic level. In this study. we completely sequenced the RhCMV strain 68-1 genome and confirmed that the virus is significantly homologous to HCMV. Data generated for the sequence analysis revealed that the genome is over 200 kb in size and is structurally similar to previously reported cytomegaloviruses. Like HCMV, RhCMV encodes a complement of immunomodulatory genes as well as structural proteins and enzymes required for replication. Unique to RhCMV is a cyclooxygenase-2 (prostaglandin E₂) homologue. Available sequence information on RhCMV will further the development of this virus as a model for HCMV pathogenesis.

Acknowledgments

This work was supported by NIH grants RR15094 (D.G.A. and S.W.W.), AI31249 (D.G.A.), RR00163 (L.I.S. and S.W.W.), and CA75922 (S.W.W.).

We thank Robert P. Searles, Jay A. Nelson, and Heather Meyers for contributions and preliminary analysis of the sequence; Klaus Früh and Peter Barry for helpful discussions during the annotation of the genome; Don Siess for technical assistance; the Wadsworth Center Molecular Genetics Core for sequencing; Andrew Townsend for graphics expertise; and Lori Boshears for proofreading the manuscript.

Acknowledgments

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