Skip to main content

Advertisement

SpringerLink
Log in

Rhesus CMV: an emerging animal model for human CMV

  • Review
  • Published:
Medical Microbiology and Immunology Aims and scope Submit manuscript

Abstract

Human CMV is the predominant infectious cause of congenital birth defects and an opportunistic pathogen in immunosuppressed individuals, including AIDS patients. Most individuals are infected early during their life followed by life-long latent infection. During this latent phase, frequent reactivation and antigen production continue to stimulate the immune system. While the immune response is able to control the virus, it is unable to eradicate it. Moreover, super-infection by different CMV strains has been observed despite a strong immune response. Long-term immune stimulation by CMV has also been implicated in immune senescence and chronic conditions such as atherosclerosis. CMVs are highly species-specific and the relatedness of CMV genomes exactly mirrors the relatedness of their hosts. Thus, each CMV species is highly adapted to its respective host species, but is unable to infect other, even closely related hosts. While fascinating from an evolutionary perspective, this host restriction prevents studying HCMV in experimental animals. Exceptions are severely immunocompromised mice, e.g. SCID mice, or SCID/NOD mice, which might allow partial reconstitution of CMV infection in rodents. More practical however, is to study CMVs in their natural host, e.g. murine, rat or guinea pig CMVs. However, while these small animal models have many advantages, such as the availability of inbred animals as well as lower cost, the limited homology of the viral genomes with HCMV limits the functional analysis of homologous gene products. The closest relative to HCMV is chimpanzee CMV (CCMV), but this is not a practical animal model since chimps are a protected species, extremely expensive and of very limited availability. In contrast, rhesus macaques are a more widely used experimental animal species and, while more distant than CCMV, rhesus CMV (RhCMV) contains most of the HCMV gene families thus allowing the study of their role in acute and latent CMV infection. In this review we will discuss the current state of developing RhCMV as a model for HCMV.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Mocarski ES, Shenk T, Pass RF (2007) Cytomegalovirus. In: Knipe DM, Howley PM, Griffin DE, Martin MA, Lamb RA, Roizman B, Straus SE (eds) Fields virology. Lippincott Williams & Wilkins, Philadelphia, pp 2701–2772

    Google Scholar 

  2. Nichols WG, Boeckh M (2000) Recent advances in the therapy and prevention of CMV infections. J Clin Virol 16:25–40

    Article  CAS  PubMed  Google Scholar 

  3. Alford CA, Stagno S, Pass RF, Britt WJ (1990) Congenital and perinatal cutomegalovirus infection. Rev Infect Dis 12:745–753

    Article  Google Scholar 

  4. Stratton KR, Durch JS, Lawrence RS (eds) (2000) Vaccines for the 21st century. National Academy Press, Washington, DC

  5. Söderberg-Naucler C, Nelson JY (1999) Human cytomegalovirus latency and reactivation—a delicate balance between the virus and its host’s immune system. Intervirology 42:314–321

    Article  PubMed  Google Scholar 

  6. Huff JL, Eberle R, Capitanio J, Zhou SS, Barry PA (2003) Differential detection of B virus and rhesus cytomegalovirus in rhesus macaques. J Gen Virol 84:83–92

    Article  CAS  PubMed  Google Scholar 

  7. Reinke P, Prosch S, Kern F, Volk HD (1999) Mechanisms of human cytomegalovirus (HCMV) (re)activation and its impact on organ transplant patients. Transpl Infect Dis 1:157–164

    Article  CAS  PubMed  Google Scholar 

  8. Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F, Sleath PR, Grabstein KH, Hosken NA, Kern F, Nelson JA, Picker LJ (2005) Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med 202:673–685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Simon CO, Holtappels R, Tervo HM, Bohm V, Daubner T, Oehrlein-Karpi SA, Kuhnapfel B, Renzaho A, Strand D, Podlech J, Reddehase MJ, Grzimek NK (2006) CD8 T cells control cytomegalovirus latency by epitope-specific sensing of transcriptional reactivation. J Virol 80:10436–10456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Streblow DN, Orloff SL, Nelson JA (2001) Do pathogens accelerate atherosclerosis?. J Nutr 131:2798S–2804S

    Article  CAS  PubMed  Google Scholar 

  11. McGeoch DJ, Cook S, Dolan A, Jamieson FE, Telford EA (1995) Molecular phylogeny and evolutionary timescale for the family of mammalian herpesviruses. J Mol Biol 247:443–458

    Article  CAS  PubMed  Google Scholar 

  12. Chee MS, Bankier AT, Beck S, Bohni R, Brown CM, Cerny R, Horsnell T, Hutchison CA 3rd, Kouzarides T, Martignetti JA et al (1990) Analysis of the protein-coding content of the sequence of human cytomegalovirus strain AD169. Curr Top Microbiol Immunol 154:125–169

    CAS  PubMed  Google Scholar 

  13. Davison AJ, Dolan A, Akter P, Addison C, Dargan DJ, Alcendor DJ, McGeoch DJ, Hayward GS (2003) The human cytomegalovirus genome revisited: comparison with the chimpanzee cytomegalovirus genome. J Gen Virol 84:17–28

    Article  CAS  PubMed  Google Scholar 

  14. Hansen SG, Strelow LI, Franchi DC, Anders DG, Wong SW (2003) Complete sequence and genomic analysis of rhesus cytomegalovirus. J Virol 77:6620–6636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rawlinson WD, Farrell HE, Barrell BG (1996) Analysis of the complete DNA sequence of murine cytomegalovirus. J Virol 70:8833–8849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Vink C, Beuken E, Bruggeman CA (2000) Complete DNA sequence of the rat cytomegalovirus genome. J Virol 74:7656–7665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. McGregor A, Liu F, Schleiss MR (2004) Identification of essential and non-essential genes of the guinea pig cytomegalovirus (GPCMV) genome via transposome mutagenesis of an infectious BAC clone. Virus Res 101:101–108

    Article  CAS  PubMed  Google Scholar 

  18. Hudson JB (1979) The murine cytomegalovirus as a model for the study of viral pathogenesis and persistent infections. Arch Virol 62:1–29

    Article  CAS  PubMed  Google Scholar 

  19. Reddehase MJ, Podlech J, Grzimek NK (2002) Mouse models of cytomegalovirus latency: overview. J Clin Virol 25(suppl 2):S23–S36

    Article  CAS  PubMed  Google Scholar 

  20. Asher DM, Gibbs CJ Jr, Lang DJ, Gajdusek DC, Chanock RM (1974) Persistent shedding of cytomegalovirus in the urine of healthy Rhesus monkeys. Proc Soc Exp Biol Med 145:794–801

    Article  CAS  PubMed  Google Scholar 

  21. Jones-Engel L, Engel GA, Heidrich J, Chalise M, Poudel N, Viscidi R, Barry PA, Allan JS, Grant R, Kyes R (2006) Temple monkeys and health implications of commensalism, Kathmandu, Nepal. Emerg Infect Dis 12:900–906

    Article  PubMed  PubMed Central  Google Scholar 

  22. Swack NS, Hsiung GD (1982) Natural and experimental simian cytomegalovirus infections at a primate center. J Med Primatol 11:169–177

    Article  CAS  PubMed  Google Scholar 

  23. Vogel P, Weigler BJ, Kerr H, Hendrickx AG, Barry PA (1994) Seroepidemiologic studies of cytomegalovirus infection in a breeding population of rhesus macaques. Lab Anim Sci 44:25–30

    CAS  PubMed  Google Scholar 

  24. Lockridge KM, Sequar G, Zhou SS, Yue Y, Mandell CP, Barry PA (1999) Pathogenesis of experimental rhesus cytomegalovirus infection. J Virol 73:9576–9583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chang WL, Tarantal AF, Zhou SS, Borowsky AD, Barry PA (2002) A recombinant rhesus cytomegalovirus expressing enhanced green fluorescent protein retains the wild-type phenotype and pathogenicity in fetal macaques. J Virol 76:9493–9504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chang WL, Barry PA (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ross SA, Fowler KB, Ashrith G, Stagno S, Britt WJ, Pass RF, Boppana SB (2006) Hearing loss in children with congenital cytomegalovirus infection born to mothers with preexisting immunity. J Pediatr 148:332–336

    Article  PubMed  Google Scholar 

  28. Barry PA, Lockridge KM, Salamat S, Tinling SP, Yue Y, Zhou SS, Gospe SM Jr, Britt WJ, Tarantal AF (2006) Nonhuman primate models of intrauterine cytomegalovirus infection. Ilar J 47:49–64

    Article  CAS  PubMed  Google Scholar 

  29. London WT, Martinez AJ, Houff SA, Wallen WC, Curfman BL, Traub RG, Sever JL (1986) Experimental congenital disease with simian cytomegalovirus in rhesus monkeys. Teratology 33:323–331

    Article  CAS  PubMed  Google Scholar 

  30. Tarantal AF, Salamat MS, Britt WJ, Luciw PA, Hendrickx AG, Barry PA (1998) Neuropathogenesis induced by rhesus cytomegalovirus in fetal rhesus monkeys (Macaca mulatta). J Infect Dis 177:446–450

    Article  CAS  PubMed  Google Scholar 

  31. Serabe BM, Murry DJ, Dauser R, Nuchtern J, Durfee J, McGuffey L, Berg S, Blaney SM (1999) Plasma and CSF pharmacokinetics of ganciclovir in nonhuman primates. Cancer Chemother Pharmacol 43:415–418

    Article  CAS  PubMed  Google Scholar 

  32. Swanson R, Bergquam E, Wong SW (1998) Characterization of rhesus cytomegalovirus genes associated with anti-viral susceptibility. Virology 240:338–348

    Article  CAS  PubMed  Google Scholar 

  33. North TW, Sequar G, Townsend LB, Drach JC, Barry PA (2004) Rhesus cytomegalovirus is similar to human cytomegalovirus in susceptibility to benzimidazole nucleosides. Antimicrob Agents Chemother 48:2760–2765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pearson TC, Trambley J, Odom K, Anderson DC, Cowan S, Bray R, Lin A, Hollenbaugh D, Aruffo A, Siadak AW, Strobert E, Hennigar R, Larsen CP (2002) Anti-CD40 therapy extends renal allograft survival in rhesus macaques. Transplantation 74:933–940

    Article  CAS  PubMed  Google Scholar 

  35. Conway MD, Didier P, Fairburn B, Soike KF, Martin L, Murphey-Corb M, Meiners N, Insler MS (1990) Ocular manifestation of simian immunodeficiency syndrome (SAIDS). Curr Eye Res 9:759–770

    Article  CAS  PubMed  Google Scholar 

  36. Henrickson RV, Maul DH, Osborn KG, Sever JL, Madden DL, Ellingsworth LR, Anderson JH, Lowenstine LJ, Gardner MB (1983) Epidemic of acquired immunodeficiency in rhesus monkeys. Lancet 1:388–390

    Article  CAS  PubMed  Google Scholar 

  37. Baskin GB (1987) Disseminated cytomegalovirus infection in immunodeficient rhesus monkeys. Am J Pathol 129:345–352

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Kaup F, Matz-Rensing K, Kuhn E, Hunerbein P, Stahl-Hennig C, Hunsmann G (1998) Gastrointestinal pathology in rhesus monkeys with experimental SIV infection. Pathobiology 66:159–164

    Article  CAS  PubMed  Google Scholar 

  39. Kuhn EM, Stolte N, Matz-Rensing K, Mach M, Stahl-Henning C, Hunsmann G, Kaup FJ (1999) Immunohistochemical studies of productive rhesus cytomegalovirus infection in rhesus monkeys (Macaca mulatta) infected with simian immunodeficiency virus. Vet Pathol 36:51–56

    Article  CAS  PubMed  Google Scholar 

  40. Kaur A, Hale CL, Noren B, Kassis N, Simon MA, Johnson RP (2002) Decreased frequency of cytomegalovirus (CMV)-specific CD4+ T lymphocytes in simian immunodeficiency virus-infected rhesus macaques: inverse relationship with CMV viremia. J Virol 76:3646–3658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kaur A, Kassis N, Hale CL, Simon M, Elliott M, Gomez-Yafal A, Lifson JD, Desrosiers RC, Wang F, Barry P, Mach M, Johnson RP (2003) Direct relationship between suppression of virus-specific immunity and emergence of cytomegalovirus disease in simian AIDS. J Virol 77:5749–5758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sequar G, Britt WJ, Lakeman FD, Lockridge KM, Tarara RP, Canfield DR, Zhou SS, Gardner MB, Barry PA (2002) Experimental coinfection of rhesus macaques with rhesus cytomegalovirus and simian immunodeficiency virus: pathogenesis. J Virol 76:7661–7671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Macchia I, Gauduin MC, Kaur A, Johnson RP (2006) Expression of CD8alpha identifies a distinct subset of effector memory CD4+ T lymphocytes. Immunology 119:232–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chan KS, Kaur A (2007) Flow cytometric detection of degranulation reveals phenotypic heterogeneity of degranulating CMV-specific CD8+ T lymphocytes in rhesus macaques. J Immunol Methods 325:20–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Pitcher CJ, Hagen SI, Walker JM, Lum R, Mitchell BL, Maino VC, Axthelm MK, Picker LJ (2002) Development and homeostasis of T cell memory in rhesus macaque. J Immunol 168:29–43

    Article  CAS  PubMed  Google Scholar 

  46. Walker JM, Maecker HT, Maino VC, Picker LJ (2004) Multicolor flow cytometric analysis in SIV-infected rhesus macaque. Methods Cell Biol 75:535–557

    Article  PubMed  Google Scholar 

  47. Kaur A, Daniel MD, Hempel D, Lee-Parritz D, Hirsch MS, Johnson RP (1996) Cytotoxic T-lymphocyte responses to cytomegalovirus in normal and simian immunodeficiency virus-infected rhesus macaques. J Virol 70:7725–7733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Estes JD, Li Q, Reynolds MR, Wietgrefe S, Duan L, Schacker T, Picker LJ, Watkins DI, Lifson JD, Reilly C, Carlis J, Haase AT (2006) Premature induction of an immunosuppressive regulatory T cell response during acute simian immunodeficiency virus infection. J Infect Dis 193:703–712

    Article  CAS  PubMed  Google Scholar 

  49. Yue Y, Zhou SS, Barry PA (2003) Antibody responses to rhesus cytomegalovirus glycoprotein B in naturally infected rhesus macaques. J Gen Virol 84:3371–3379

    Article  CAS  PubMed  Google Scholar 

  50. Rivailler P, Kaur A, Johnson RP, Wang F (2006) Genomic sequence of rhesus cytomegalovirus 180.92: insights into the coding potential of rhesus cytomegalovirus. J Virol 80:4179–4182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Cha TA, Tom E, Kemble GW, Duke GM, Mocarski ES, Spaete RR (1996) Human cytomegalovirus clinical isolates carry at least 19 genes not found in laboratory strains. J Virol 70:78–83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Murphy E, Rigoutsos I, Shibuya T, Shenk TE (2003) Reevaluation of human cytomegalovirus coding potential. Proc Natl Acad Sci USA 100:13585–13590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pande NT, Powers C, Ahn K, Fruh K (2005) Rhesus cytomegalovirus contains functional homologues of US2, US3, US6, and US11. J Virol 79:5786–5798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Alcendor DJ, Barry PA, Pratt-Lowe E, Luciw PA (1993) Analysis of the rhesus cytomegalovirus immediate-early gene promoter. Virology 194:815–821

    Article  CAS  PubMed  Google Scholar 

  55. Barry PA, Alcendor DJ, Power MD, Kerr H, Luciw PA (1996) Nucleotide sequence and molecular analysis of the rhesus cytomegalovirus immediate-early gene and the UL121–117 open reading frames. Virology 215:61–72

    Article  CAS  PubMed  Google Scholar 

  56. Kravitz RH, Sciabica KS, Cho K, Luciw PA, Barry PA (1997) Cloning and characterization of rhesus cytomegalovirus glycoprotein B. J Gen Virol 78(Pt 8):2009–2013

    Article  CAS  PubMed  Google Scholar 

  57. Kropff B, Mach M (1997) Identification of the gene coding for rhesus cytomegalovirus glycoprotein B and immunological analysis of the protein. J Gen Virol 78(Pt 8):1999–2007

    Article  CAS  PubMed  Google Scholar 

  58. Yue Y, Kaur A, Zhou SS, Barry PA (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

    Article  CAS  PubMed  Google Scholar 

  59. McCormick AL, Skaletskaya A, Barry PA, Mocarski ES, Goldmacher VS (2003) Differential function and expression of the viral inhibitor of caspase 8-induced apoptosis (vICA) and the viral mitochondria-localized inhibitor of apoptosis (vMIA) cell death suppressors conserved in primate and rodent cytomegaloviruses. Virology 316:221–233

    Article  CAS  PubMed  Google Scholar 

  60. Lockridge KM, Zhou SS, Kravitz RH, Johnson JL, Sawai ET, Blewett EL, Barry PA (2000) Primate cytomegaloviruses encode and express an IL-10-like protein. Virology 268:272–280

    Article  CAS  PubMed  Google Scholar 

  61. Spencer JV, Lockridge KM, Barry PA, Lin G, Tsang M, Penfold ME, Schall TJ (2002) Potent immunosuppressive activities of cytomegalovirus-encoded interleukin-10. J Virol 76:1285–1292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Penfold ME, Schmidt TL, Dairaghi DJ, Barry PA, Schall TJ (2003) Characterization of the rhesus cytomegalovirus US28 locus. J Virol 77:10404–10413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lesniewski M, Das S, Skomorovska-Prokvolit Y, Wang FZ, Pellett PE (2006) Primate cytomegalovirus US12 gene family: a distinct and diverse clade of seven-transmembrane proteins. Virology 354:286–298

    Article  CAS  PubMed  Google Scholar 

  64. Rue CA, Jarvis MA, Knoche AJ, Meyers HL, DeFilippis VR, Hansen SG, Wagner M, Fruh K, Anders DG, Wong SW, Barry PA, Nelson JA (2004) A cyclooxygenase-2 homologue encoded by rhesus cytomegalovirus is a determinant for endothelial cell tropism. J Virol 78:12529–12536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Zhu H, Cong JP, Yu D, Bresnahan WA, Shenk TE (2002) Inhibition of cyclooxygenase 2 blocks human cytomegalovirus replication. Proc Natl Acad Sci USA 99:3932–3937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. DeFilippis V, Fruh K (2005) Rhesus cytomegalovirus particles prevent activation of interferon regulatory factor 3. J Virol 79:6419–6431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chang WL, Kirchoff V, Pari GS, Barry PA (2002) Replication of rhesus cytomegalovirus in life-expanded rhesus fibroblasts expressing human telomerase. J Virol Methods 104:135–146

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Vaccine and Gene Therapy Institute, Oregon Health and Science University, 505 NW 185th Ave., Beaverton, OR, 97006, USA

    Colin Powers & Klaus Früh

Authors
  1. Colin Powers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Klaus Früh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Klaus Früh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Powers, C., Früh, K. Rhesus CMV: an emerging animal model for human CMV. Med Microbiol Immunol 197, 109–115 (2008). https://doi.org/10.1007/s00430-007-0073-y

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00430-007-0073-y

Keywords

Search

Navigation