Kidney epithelial cells are common targets for human and rhesus cytomegalovirus (HCMV and RhCMV) in vivo, and represent an important reservoir for long-term CMV shedding in urine. To better understand the role of kidney epithelial cells in primate CMV natural history, primary cultures of rhesus macaque kidney epithelial cells (MKE) were established and tested for infectivity by five RhCMV strains, including two wild-type strains (UCD52 and UCD59) and three strains containing different coding contents in UL/b′. The latter strains included 180.92 [containing an intact RhUL128-RhUL130-R hUL131 (RhUL128L) locus but deleted for the UL/b′ RhUL148–rh167-loci], 68-1 (RhUL128L-defective and fibroblast-tropic) and BRh68-1.2 (the RhUL128L-repaired version of 68-1). As demonstrated by RhCMV cytopathic effect, plaque formation, growth kinetics and early virus entry, we showed that MKE were differentially susceptible to RhCMV infection, related to UL/b′ coding contents of the different strains. UCD52 and UCD59 replicated vigorously in MKE, 68-1 replicated poorly, and 180.92 grew with intermediate kinetics. Reconstitution of RhUL128L in 68-1 (BRh68-1.2) restored its replication efficiency in MKE as compared to UCD52 and UCD59, consistent with the essential role of UL128L for HCMV epithelial tropism. Further analysis revealed that the UL/b′ UL148-rh167-loci deletion in 180.92 impaired RhUL132 (rh160) expression. Given that 180.92 retains an intact RhUL128L, but genetically or functionally lacks genes from RhUL132 (rh160) to rh167 in UL/b′, its attenuated infection efficiency indicated that, along with RhUL128L, an additional protein(s) encoded within the UL/b′ RhUL132 (rh160)-rh167 region (potentially, RhUL132 and/or RhUL148) is indispensable for efficient replication in MKE.
AdlerB., ScrivanoL., RuzcicsZ., RuppB., SinzgerC., KoszinowskiU.2006; Role of human cytomegalovirus UL131A in cell type-specific virus entry and release. J Gen Virol 87:2451–2460 [View Article][PubMed]
BaerP. C., Bereiter-HahnJ., SchubertR., GeigerH.2006; Differentiation status of human renal proximal and distal tubular epithelial cells in vitro: Differential expression of characteristic markers. Cells Tissues Organs 184:16–22 [View Article][PubMed]
BodaghiB., Slobbe-van DrunenM. E., TopilkoA., PerretE., VossenR. C., van Dam-MierasM. C., ZipetoD., VirelizierJ. L., LeHoangP., BruggemanC. A., MichelsonS.1999; Entry of human cytomegalovirus into retinal pigment epithelial and endothelial cells by endocytosis. InvestOphthalmol Vis Sci 40:2598–2607
ChaT. A., TomE., KembleG. W., DukeG. M., MocarskiE. S., SpaeteR. R.1996; Human cytomegalovirus clinical isolates carry at least 19 genes not found in laboratory strains. J Virol 70:78–83[PubMed]
ChangW. L., BarryP. A.2003; Cloning of the full-length rhesus cytomegalovirus genome as an infectious and self-excisable bacterial artificial chromosome for analysis of viral pathogenesis. J Virol 77:5073–5083[PubMed]
CheungT. C., HumphreysI. R., PotterK. G., NorrisP. S., ShumwayH. M., TranB. R., PattersonG., Jean-JacquesR., YoonM., SpearP. G., MurphyK. M., LurainN. S., BenedictC. A., WareC. F.2005; Evolutionarily divergent herpesviruses modulate T cell activation by targeting the herpesvirus entry mediator cosignaling pathway. Proc Natl Acad Sci U S A 102:13218–13223 [View Article]
CunninghamC., GathererD., HilfrichB., BaluchovaK., DarganD. J., ThomsonM., GriffithsP. D., WilkinsonG. W., SchulzT. F., DavisonA. J.2010; Sequences of complete human cytomegalovirus genomes from infected cell cultures and clinical specimens. J Gen Virol 91:605–615 [View Article][PubMed]
Elkouby-NaorL., Ben-YosefT.2010; Functions of claudin tight junction proteins and their complex interactions in various physiological systems. Int Rev Cell Mol Biol 279:1–32 [View Article][PubMed]
HahnG., RevelloM. G., PatroneM., PercivalleE., CampaniniG., SarasiniA., WagnerM., GallinaA., MilanesiG., KoszinowskiU., BaldantiF., GernaG.2004; Human cytomegalovirus UL131-128 genes are indispensable for virus growth in endothelial cells and virus transfer to leukocytes. J Virol 78:10023–10033 [View Article][PubMed]
JarvisM. A., WangC. E., MeyersH. L., SmithP. P., CorlessC. L., HendersonG. J., VieiraJ., BrittW. J., NelsonJ. A.1999; Human cytomegalovirus infection of caco-2 cells occurs at the basolateral membrane and is differentiation state dependent. J Virol 73:4552–4560[PubMed]
JarvisM. A., NelsonJ. A.2007; Human cytomegalovirus tropism for endothelial cells: Not all endothelial cells are created equal. J Virol 81:2095–2101 [View Article][PubMed]
KirchoffV., WongS., StJ. S., PariG. S.2002; Generation of a life-expanded rhesus monkey fibroblast cell line for the growth of rhesus rhadinovirus (RRV). Arch Virol 147:321–333[PubMed]
LiG., NguyenC. C., RyckmanB. J., BrittW. J., KamilJ. P.2015; A viral regulator of glycoprotein complexes contributes to human cytomegalovirus cell tropism. Proc Natl Acad Sci U S A 112:4471–4476 [View Article][PubMed]
LiljaA. E., ShenkT.2008; Efficient replication of rhesus cytomegalovirus variants in multiple rhesus and human cell types. Proc Natl Acad Sci U S A 105:19950–19955
LurainN. S., FoxA. M., LichyH. M., BhoradeS. M., WareC. F., HuangD. D., KwanS. P., GarrityE. R., ChouS.2006; Analysis of the human cytomegalovirus genomic region from UL146 through UL147A reveals sequence hypervariability, genotypic stability, and overlapping transcripts. Virol J 3, :4 [View Article][PubMed]
McCormickA. L., RobackL., Livingston-RosanoffD., St ClairC.2010; The human cytomegalovirus UL36 gene controls caspase-dependent and -independent cell death programs activated by infection of monocytes differentiating to macrophages. J Virol 84:5108–5123 [View Article][PubMed]
MillardA. L., HäberliL., SinzgerC., GhielmettiM., SchneiderM. K., BossartW., SeebachJ. D., MuellerN. J., HaberliL.2010; Efficiency of porcine endothelial cell infection with human cytomegalovirus depends on both virus tropism and endothelial cell vascular origin. Xenotransplantation 17:274–287 [View Article][PubMed]
OxfordK. L., EberhardtM. K., YangK. W., StrelowL., KellyS., ZhouS. S., BarryP. A.2008; Protein coding content of the ULb′ region of wild-type rhesus cytomegalovirus. Virology (Auckl) 373:181–188 [View Article][PubMed]
OxfordK. L., StrelowL., YueY., ChangW. L., SchmidtK. A., DiamondD. J., BarryP. A.2011; Open reading frames carried on ULb′ are implicated in shedding and horizontal transmission of rhesus cytomegalovirus in rhesus monkeys. J Virol 85:5105–5114 [View Article][PubMed]
PenfoldM. E. T., DairaghiD. J., DukeG. M., SaederupN., MocarskiE. S., KembleG. W., SchallT. J.1999; Cytomegalovirus encodes a potent a chemokine. Proc Natl Acad Sci U S A 96:9839–9844
PerefarresF., ThebaudG., LefeuvreP., ChiroleuF., RimbaudL., HoareauM., ReynaudB., LettJ. M.2014; Frequency-dependent assistance as a way out of competitive exclusion between two strains of an emerging virus. Proc Biol Sci 281:2013–3374 [View Article]
PrichardM. N., PenfoldM. E., DukeG. M., SpaeteR. R., KembleG. W.2001; A review of genetic differences between limited and extensively passaged human cytomegalovirus strains. Rev Med Virol 11:191–200[PubMed]
Prod'hommeV., SugrueD. M., StantonR. J., NomotoA., DaviesJ., RickardsC. R., CochraneD., MooreM., WilkinsonG. W., TomasecP.2010; Human cytomegalovirus UL141 promotes efficient downregulation of the natural killer cell activating ligand CD112. J Gen Virol 91:2034–2039 [View Article][PubMed]
RyckmanB. J., JarvisM. A., DrummondD. D., NelsonJ. A., JohnsonD. C.2006; Human cytomegalovirus entry into epithelial and endothelial cells depends on genes UL128 to UL150 and occurs by endocytosis and low-pH fusion. J Virol 80:710–722 [View Article][PubMed]
RyckmanB. J., RainishB. L., ChaseM. C., BortonJ. A., NelsonJ. A., JarvisM. A., JohnsonD. C.2008; Characterization of the human cytomegalovirus gH/gL/UL128-131 complex that mediates entry into epithelial and endothelial cells. J Virol 82:60–70 [View Article][PubMed]
SinzgerC., KahlM., LaibK., KlingelK., RiegerP., PlachterB., JahnG.2000; Tropism of human cytomegalovirus for endothelial cells is determined by a post-entry step dependent on efficient translocation to the nucleus. J Gen Virol 81:3021–3035 [View Article][PubMed]
SpadernaS., KropffB., KödelY., ShenS., ColeyS., LuS., BrittW., MachM., KodelY.2005; Deletion of gpUL132, a structural component of human cytomegalovirus, results in impaired virus replication in fibroblasts. J Virol 79:11837–11847 [View Article][PubMed]
StantonR. J., BaluchovaK., DarganD. J., CunninghamC., SheehyO., SeirafianS., McSharryB. P., NealeM. L., DaviesJ. A., TomasecP., DavisonA. J., WilkinsonG. W.2010; Reconstruction of the complete human cytomegalovirus genome in a BAC reveals RL13 to be a potent inhibitor of replication. J Clin Invest 120: [View Article][PubMed]
TugizovS., MaidjiE., PereiraL.1996; Role of apical and basolateral membranes in replication of human cytomegalovirus in polarized retinal pigment epithelial cells. J Gen Virol 77: (Pt 1) 61–74 [View Article][PubMed]
VogelP., WeiglerB. J., KerrH., HendrickxA. G., BarryP. A.1994; Seroepidemiologic studies of cytomegalovirus infection in a breeding population of rhesus macaques. Lab Anim Sci 44:25–30[PubMed]
WangD., ShenkT.2005; Human cytomegalovirus virion protein complex required for epithelial and endothelial cell tropism. Proc Natl Acad Sci U S A 102:18153–18158 [View Article][PubMed]
WangD., YuQ. C., SchröerJ., MurphyE., ShenkT.2007; Human cytomegalovirus uses two distinct pathways to enter retinal pigmented epithelial cells. Proc Natl Acad Sci U S A 104:20037–20042 [View Article][PubMed]
WussowF., YueY., MartinezJ., DeereJ. D., LongmateJ., HerrmannA., BarryP. A., DiamondD. J.2013; A vaccine based on the rhesus cytomegalovirus UL128 complex induces broadly neutralizing antibodies in rhesus macaques. J Virol 87:1322–1332 [View Article][PubMed]
YueY., KaurA., ZhouS. S., BarryP. A.2006; Characterization and immunological analysis of the rhesus cytomegalovirus homologue (Rh112) of the human cytomegalovirus UL83 lower matrix phosphoprotein (pp65). J Gen Virol 87:777–787 [View Article][PubMed]
YueY., BarryP. A.2008; Rhesus cytomegalovirus a nonhuman primate model for the study of human cytomegalovirus. Adv Virus Res 72:207–226 [View Article][PubMed]