title: Limited dissemination and shedding of the UL128 complex-intact, UL/b'-defective rhesus cytomegalovirus strain 180.92.
abstract: The UL128 complex of human cytomegalovirus (CMV) is a major determinant of viral entry into epithelial and endothelial cells and a target for vaccine development. The UL/b' region of rhesus CMV contains several open reading frames, including orthologs of the UL128 complex. We recently showed that the coding content of the rhesus CMV (RhCMV) UL/b' region predicts acute endothelial tropism and long-term shedding in vivo in the rhesus macaque model of CMV infection. The laboratory-passaged RhCMV 180.92 strain has a truncated UL/b' region but an intact UL128 complex. To investigate whether the presence of the UL128 complex alone was sufficient to confer endothelial and epithelial tropism in vivo, we investigated tissue dissemination and viral excretion following experimental RhCMV 180.92 inoculation of RhCMV-seronegative rhesus macaques. We show the presence of at least two virus variants in the RhCMV 180.92 infectious virus stock. A rare variant noted for a nontruncated wild-type-virus-like UL/b' region, rapidly emerged during in vivo replication and showed high-level replication in blood and tissues and excretion in urine and saliva, features similar to those previously reported in naturally occurring wild-type RhCMV infection. In contrast, the predominant truncated version of RhCMV 180.92 showed significantly lower plasma DNAemia and limited tissue dissemination and viral shedding. These data demonstrate that the truncated RhCMV 180.92 variant is attenuated in vivo and suggest that additional UL/b' genes, besides the UL128 complex, are required for optimal in vivo CMV replication and dissemination.
  
  
  OBJECTIVE
  An effective vaccine against human CMV infection will need to target genes that are essential for virus propagation and transmission. The human CMV UL128 complex represents one such candidate antigen since it is essential for endothelial and epithelial cell tropism, and is a target for neutralizing antibodies in CMV-infected individuals. In this study, we used the rhesus macaque animal model of CMV infection to investigate the in vivo function of the UL128 complex. Using experimental infection of rhesus macaques with a rhesus CMV virus variant that contained an intact UL128 complex but was missing several other genes, we show that the presence of the UL128 complex alone is not sufficient for widespread tissue dissemination and virus excretion. These data highlight the importance of in vivo studies in evaluating human CMV gene function and suggest that additional UL/b' genes are required for optimal CMV dissemination and transmission.
authors.affiliation: Division of Comparative Pathology, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA Center for Comparative Medicine, University of California, Davis, Davis, California, USA.
authors.forename: Basel T
authors.initials: BT
authors.lastname: Assaf
authors.affiliation: Division of Comparative Pathology, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA.
authors.forename: Keith G
authors.initials: KG
authors.lastname: Mansfield
authors.affiliation: Center for Comparative Medicine, University of California, Davis, Davis, California, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Strelow
authors.affiliation: Division of Comparative Pathology, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA.
authors.forename: Susan V
authors.initials: SV
authors.lastname: Westmoreland
authors.affiliation: Center for Comparative Medicine, University of California, Davis, Davis, California, USA Department of Pathology and Laboratory Medicine, University of California, Davis, Davis, California, USA California National Primate Research Center, University of California, Davis, Davis, California, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Barry
authors.affiliation: Division of Immunology, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA amitinder_kaur@hms.harvard.edu.
authors.forename: Amitinder
authors.initials: A
authors.lastname: Kaur
mesh_terms: D000818:Animals; D002460:Cell Line; D003587:Cytomegalovirus / Q000235:genetics* / Q000378:metabolism*; D003586:Cytomegalovirus Infections / Q000821:virology; D004195:Disease Models, Animal; D004727:Endothelium / Q000821:virology; D004848:Epithelium / Q000821:virology; D005347:Fibroblasts / Q000821:virology; D006801:Humans; D008253:Macaca mulatta / Q000821:virology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism* / Q000652:urine; D016366:Open Reading Frames; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000378:metabolism* / Q000652:urine; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism* / Q000652:urine; D056189:Viral Tropism / Q000235:genetics; D014779:Virus Replication / Q000235:genetics; D017201:Virus Shedding / Q000235:genetics*
chemical_list: D008562:Membrane Glycoproteins; C532797:UL128 protein, human cytomegalovirus; D014759:Viral Envelope Proteins; D014764:Viral Proteins