Complete Sequence and Genomic Analysis of Rhesus Cytomegalovirus

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 advanta...

Rhesus CMV: an emerging animal model for human CMV

“…The RhCMV genome (strain 68.1) is 221,459 bp in length, slightly smaller than HCMVs 229,354 bp [14]. The genomes are colinear and share a similar structure, although unlike HCMV, RhCMV does not appear to isomerize [14].…”

“…Both the UL36 (viral inhibitor of caspase-8-induced apoptosis, vICA) and UL37 (mitochondria inhibitor of apoptosis, vMIA) homologs in RhCMV were able to prevent Fas-mediated apoptosis in HeLa cells, whereas the MCMV UL37 homolog M37 was not [59]. The IL-10 homolog of CMVs was Wrst identiWed in RhCMV and was shown to be expressed in vivo, targeted by the humoral immune response, and to have [14] and [50] immunosuppressive properties [60,61]. RhCMV also contains homologs of HCMV US2, US3, US6, and US11 [53].…”

“…The genomes are colinear and share a similar structure, although unlike HCMV, RhCMV does not appear to isomerize [14]. Initially 230 open reading frames (ORFs) were predicted within strain 68.1, although this number was later proposed to be modiWed to 260 [50].…”

“…Large loci of RhCMV-speciWc genes are located at the ends of the RhCMV genome and in the rh165-180 ORFs, a region at the same position as the U L /bЈ region of HCMV, which is deleted or truncated in laboratory strains [51]. There are currently two full-length RhCMV strains sequenced [14,50].…”

“…This species-speciWcity is a characteristic trait of -herpesviruses in general, and therefore, viral evolution has accompanied mammalian speciation such that each species has their own uniquely adapted CMV, and CMV relatedness generally parallels species relatedness [11]. Thus, the genomes of primate CMVs (human [12], chimp [13], rhesus [14]) are much more closely related to each other than rodent CMVs (mouse [15], rat [16], guinea pig [17]). Consequently, animal models for CMV depend on studying the CMVs of the respective mammal species.…”