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Pathogenesis of human cytomegalovirus in the immunocompromised host

Nature Reviews Microbiology volume 19, pages 759–773 (2021)Cite this article

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Abstract

Human cytomegalovirus (HCMV) is a herpesvirus that infects ~60% of adults in developed countries and more than 90% in developing countries. Usually, it is controlled by a vigorous immune response so that infections are asymptomatic or symptoms are mild. However, if the immune system is compromised, HCMV can replicate to high levels and cause serious end organ disease. Substantial progress is being made in understanding the natural history and pathogenesis of HCMV infection and disease in the immunocompromised host. Serial measures of viral load defined the dynamics of HCMV replication and are now used routinely to allow intervention with antiviral drugs in individual patients. They are also used as pharmacodynamic read-outs to evaluate prototype vaccines that may protect against HCMV replication and to define immune correlates of this protection. This novel information is informing the design of randomized controlled trials of new antiviral drugs and vaccines currently under evaluation. In this Review, we discuss immune responses to HCMV and countermeasures deployed by the virus, the establishment of latency and reactivation from it, exogenous reinfection with additional strains, pathogenesis, development of end organ disease, indirect effects of infection, immune correlates of control of replication, current treatment strategies and the evaluation of novel vaccine candidates.

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Fig. 1: Overview of human cytomegalovirus entry into target cells and the establishment of latency in non-permissive myeloid cells.
Fig. 2: Viral and host functions in human cytomegalovirus latency and reactivation.
Fig. 3: Prevalence of human cytomegalovirus antibodies and incidence of infection in immunocompromised individuals.
Fig. 4: Distribution of peak viral loads in immunocompromised individuals.
Fig. 5: Two distinct strategies used to reduce human cytomegalovirus disease in allograft recipients.

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References

  1. Zuhair, M. et al. Estimation of the worldwide seroprevalence of cytomegalovirus: a systematic review and meta-analysis. Rev. Med. Virol. 29, e2034 (2019).

    PubMed  Google Scholar 

  2. Pembrey, L. et al. Seroprevalence of cytomegalovirus, Epstein Barr virus and varicella zoster virus among pregnant women in Bradford: a cohort study. PLoS ONE 8, e81881 (2013).

    PubMed  PubMed Central  Google Scholar 

  3. Pembrey, L. et al. Cytomegalovirus, Epstein–Barr virus and varicella zoster virus infection in the first two years of life: a cohort study in Bradford, UK. BMC Infect. Dis. 17, 220 (2017).

    PubMed  PubMed Central  Google Scholar 

  4. Staras, S. A. et al. Cytomegalovirus seroprevalence and childhood sources of infection: a population-based study among pre-adolescents in the United States. J. Clin. Virol. 43, 266–271 (2008).

    PubMed  Google Scholar 

  5. Griffiths, P. D., McLean, A. & Emery, V. C. Encouraging prospects for immunisation against primary cytomegalovirus infection. Vaccine 19, 1356–1362 (2001). This article presents the first calculation of the basic reproductive number for HCMV, showing that only 60% of the population have to be rendered immune to achieve herd immunity.

    CAS  PubMed  Google Scholar 

  6. Colugnati, F. A., Staras, S. A., Dollard, S. C. & Cannon, M. J. Incidence of cytomegalovirus infection among the general population and pregnant women in the United States. BMC Infect. Dis. 7, 71 (2007).

    PubMed  PubMed Central  Google Scholar 

  7. Mayer, B. T. et al. Transient Oral Human Cytomegalovirus Infections Indicate Inefficient Viral Spread from Very Few Initially Infected Cells. J. Virol. 91, e00380–17 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Staras, S. A. et al. Influence of sexual activity on cytomegalovirus seroprevalence in the United States, 1988–1994. Sex. Transm. Dis. 35, 472–479 (2008).

    PubMed  Google Scholar 

  9. Atabani, S. F. et al. Cytomegalovirus replication kinetics in solid organ transplant recipients managed by preemptive therapy. Am. J. Transplant. 12, 2457–2464 (2012). This article presents a large cohort study of patients with renal or liver transplantation managed exclusively with PET showing multiple parameters of HCMV viral load.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Griffiths, P. The direct and indirect consequences of cytomegalovirus infection and potential benefits of vaccination. Antivir. Res. 176, 104732 (2020).

    CAS  PubMed  Google Scholar 

  11. Cannon, M. J. & Davis, K. F. Washing our hands of the congenital cytomegalovirus disease epidemic. BMC Public Health 5, 70 (2005). This article clearly demonstrates that HCMV is less well recognized by the general public than other conditions that are medically less important.

    PubMed  PubMed Central  Google Scholar 

  12. Boeckh, M. & Nichols, W. G. The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood 103, 2003–2008 (2004). This article clearly describes the excess mortality seen in SCT patients with HCMV.

    CAS  PubMed  Google Scholar 

  13. Deayton, J. R. et al. Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy. Lancet 363, 2116–2121 (2004). This prospective cohort study shows that mortality in individuals who are HIV-positive is driven by the CD4+ T cell count and HCMV rather than by HIV.

    CAS  PubMed  Google Scholar 

  14. Fielding, C. A. et al. Control of immune ligands by members of a cytomegalovirus gene expansion suppresses natural killer cell activation. Elife 6, e22206 (2017).

    PubMed  PubMed Central  Google Scholar 

  15. Patel, M. et al. HCMV-encoded NK modulators: lessons from in vitro and in vivo genetic variation. Front. Immunol. 9, 2214 (2018).

    PubMed  PubMed Central  Google Scholar 

  16. Berry, R., Watson, G. M., Jonjic, S., Degli-Esposti, M. A. & Rossjohn, J. Modulation of innate and adaptive immunity by cytomegaloviruses. Nat. Rev. Immunol. 20, 113–127 (2020).

    CAS  PubMed  Google Scholar 

  17. Jackson, S. E. et al. Latent cytomegalovirus (CMV) infection does not detrimentally alter T cell responses in the healthy old, but increased latent CMV carriage is related to expanded CMV-specific T cells. Front. Immunol. 8, 733 (2017).

    PubMed  PubMed Central  Google Scholar 

  18. Prod’homme, V. et al. The human cytomegalovirus MHC class I homolog UL18 inhibits LIR-1+ but activates LIR-1– NK cells. J. Immunol. 178, 4473–4481 (2007).

    PubMed  Google Scholar 

  19. Prod’homme, V. et al. Human cytomegalovirus UL141 promotes efficient downregulation of the natural killer cell activating ligand CD112. J. Gen. Virol. 91, 2034–2039 (2010).

    PubMed  PubMed Central  Google Scholar 

  20. Kubin, M. et al. ULBP1, 2, 3: novel MHC class I-related molecules that bind to human cytomegalovirus glycoprotein UL16, activate NK cells. Eur. J. Immunol. 31, 1428–1437 (2001).

    CAS  PubMed  Google Scholar 

  21. Tomasec, P. et al. Downregulation of natural killer cell-activating ligand CD155 by human cytomegalovirus UL141. Nat. Immunol. 6, 181-UL188 (2005).

    Google Scholar 

  22. Cosman, D. et al. ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14, 123–133 (2001).

    CAS  PubMed  Google Scholar 

  23. Lilley, B. N., Ploegh, H. L. & Tirabassi, R. S. Human cytomegalovirus open reading frame TRL11/IRL11 encodes an immunoglobulin G Fc-binding protein. J. Virol. 75, 11218–11221 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Atalay, R. et al. Identification and expression of human cytomegalovirus transcription units coding for two distinct Fcγ receptor homologs. J. Virol. 76, 8596–8608 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. McSharry, B. P., Avdic, S. & Slobedman, B. Human cytomegalovirus encoded homologs of cytokines, chemokines and their receptors: roles in immunomodulation. Viruses. 4, 2448–2470 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Klenerman, P. & Hill, A. T cells and viral persistence: lessons from diverse infections. Nat. Immunol. 6, 873–879 (2005).

    CAS  PubMed  Google Scholar 

  27. Goodrum, F. Human cytomegalovirus latency: approaching the Gordian knot. Annu. Rev. Virol. 3, 333–357 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Dupont, L. & Reeves, M. B. Cytomegalovirus latency and reactivation: recent insights into an age old problem. Rev. Med. Virol. 26, 75–89 (2016).

    PubMed  Google Scholar 

  29. Jarvis, M. A. & Nelson, J. A. Human cytomegalovirus persistence and latency in endothelial cells and macrophages. Curr. Opin. Microbiol. 5, 403–407 (2002).

    CAS  PubMed  Google Scholar 

  30. Soderberg-Naucler, C., Fish, K. N. & Nelson, J. A. Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell 91, 119–126 (1997).

    CAS  PubMed  Google Scholar 

  31. Taylor-Wiedeman, J., Sissons, P. & Sinclair, J. Induction of endogenous human cytomegalovirus gene expression after differentiation of monocytes from healthy carriers. J. Virol. 68, 1597–1604 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Reeves, M. B., MacAry, P. A., Lehner, P. J., Sissons, J. G. & Sinclair, J. H. Latency, chromatin remodeling, and reactivation of human cytomegalovirus in the dendritic cells of healthy carriers. Proc. Natl Acad. Sci. USA 102, 4140–4145 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Hahn, G., Jores, R. & Mocarski, E. S. Cytomegalovirus remains latent in a common precursor of dendritic and myeloid cells. Proc. Natl Acad. Sci. USA 95, 3937–3942 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Lathey, J. L. & Spector, S. A. Unrestricted replication of human cytomegalovirus in hydrocortisone-treated macrophages. J. Virol. 65, 6371–6375 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Weinshenker, B. G., Wilton, S. & Rice, G. P. Phorbol ester-induced differentiation permits productive human cytomegalovirus infection in a monocytic cell line. J. Immunol. 140, 1625–1631 (1988).

    CAS  PubMed  Google Scholar 

  36. Prosch, S., Docke, W. D., Reinke, P., Volk, H. D. & Kruger, D. H. Human cytomegalovirus reactivation in bone-marrow-derived granulocyte/monocyte progenitor cells and mature monocytes. Intervirology 42, 308–313 (1999).

    CAS  PubMed  Google Scholar 

  37. Reeves, M. B. & Compton, T. Inhibition of inflammatory interleukin-6 activity via extracellular signal-regulated kinase-mitogen-activated protein kinase signaling antagonizes human cytomegalovirus reactivation from dendritic cells. J. Virol. 85, 12750–12758 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Hargett, D. & Shenk, T. E. Experimental human cytomegalovirus latency in CD14+ monocytes. Proc. Natl Acad. Sci. USA 107, 20039–20044 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Mansfield, S., Griessl, M., Gutknecht, M. & Cook, C. H. Sepsis and cytomegalovirus: foes or conspirators? Med. Microbiol. Immunol. 204, 431–437 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Li, X. et al. Cytomegalovirus infection and outcome in immunocompetent patients in the intensive care unit: a systematic review and meta-analysis. BMC Infect. Dis. 18, 289 (2018).

    PubMed  PubMed Central  Google Scholar 

  41. Ljungman, P. et al. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin. Infect. Dis. 64, 87–91 (2017).

    PubMed  Google Scholar 

  42. Holland, G. N. Immune recovery uveitis. Ocul. Immunol. Inflamm. 7, 215–221 (1999).

    CAS  PubMed  Google Scholar 

  43. Boeckh, M. et al. Cytomegalovirus (CMV) DNA quantitation in bronchoalveolar lavage fluid from hematopoietic stem cell transplant recipients with CMV pneumonia. J. Infect. Dis. 215, 1514–1522 (2017). This prospective study collects bronchoalveolar lavage samples from SCT patients with HCMV pneumonitis and those who were well to demonstrate the high viral load associated with pneumonitis.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Grundy, J. E., Shanley, J. D. & Griffiths, P. D. Is cytomegalovirus interstitial pneumonitis in transplant recipients an immunopathological condition? Lancet 2, 996–999 (1987).

    CAS  PubMed  Google Scholar 

  45. Hill, R. B. Jr., Rowlands, D. T. Jr. & Rifkind, D. Infectious pulmonary disease in patients receiving immunosuppressive therapy for organ transplantation. N. Engl. J. Med. 271, 1021–1027 (1964).

    PubMed  Google Scholar 

  46. Cope, A. V. et al. Quantity of cytomegalovirus viruria is a major risk factor for cytomegalovirus disease after renal transplantation. J.Med.Virol. 52, 200–205 (1997).

    CAS  PubMed  Google Scholar 

  47. Cope, A. V. et al. Interrelationships among quantity of human cytomegalovirus (HCMV) DNA in blood, donor–recipient serostatus, and administration of methylprednisolone as risk factors for HCMV disease following liver transplantation. J. Infect. Dis. 176, 1484–1490 (1997).

    CAS  PubMed  Google Scholar 

  48. Grundy, J. E. et al. Symptomatic cytomegalovirus infection in seropositive kidney recipients: reinfection with donor virus rather than reactivation of recipient virus. Lancet 2, 132–135 (1988). This study of multiple recipients from groups of kidney donors shows how typing of HCMV strains can prove reinfection of recipients who are seropositive.

    CAS  PubMed  Google Scholar 

  49. Hasing, M. E., Pang, X. L., Mabilangan, C. & Preiksaitis, J. K. Donor cytomegalovirus transmission patterns in solid organ transplant recipients with primary infection. J. Infect. Dis. 223, 827–837 (2021).

    PubMed  Google Scholar 

  50. Panagou, E. et al. Cytomegalovirus pre-emptive therapy after hematopoietic stem cell transplantation in the era of real-time quantitative PCR: comparison with recipients of solid organ transplants. Transpl. Infect. Dis. 18, 405–414 (2016).

    CAS  PubMed  Google Scholar 

  51. Slobedman, B. & Mocarski, E. S. Quantitative analysis of latent human cytomegalovirus. J. Virol. 73, 4806–4812 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Grob, J. P. et al. Immune donors can protect marrow-transplant recipients from severe cytomegalovirus infections. Lancet 1, 774–776 (1987).

    CAS  PubMed  Google Scholar 

  53. Wimperis, J. Z. et al. Transfer of a functioning humoral immune system in transplantation of T-lymphocyte-depleted bone marrow. Lancet 1, 339–343 (1986).

    CAS  PubMed  Google Scholar 

  54. Gor, D. et al. Longitudinal fluctuations in cytomegalovirus load in bone marrow transplant patients: relationship between peak virus load, donor/recipient serostatus, acute GVHD and CMV disease. Bone Marrow Transpl. 21, 597–605 (1998).

    CAS  Google Scholar 

  55. Duke, E. R. et al. Cytomegalovirus viral load kinetics as surrogate endpoints after allogeneic transplantation. J. Clin. Invest. 131, 1 (2020).

    Google Scholar 

  56. Natori, Y. et al. Use of viral load as a surrogate marker in clinical studies of cytomegalovirus in solid organ transplantation: a systematic review and meta-analysis. Clin. Infect. Dis. 66, 617–631 (2018). This systematic analysis of the published literature shows that the HCMV viral load meets the predefined criteria laid down by regulators to be accepted as a surrogate biomarker for EOD.

    CAS  PubMed  Google Scholar 

  57. Griffiths, P. D. et al. Randomized controlled trials to define viral load thresholds for cytomegalovirus pre-emptive therapy. PLoS ONE 11, e0163722 (2016).

    PubMed  PubMed Central  Google Scholar 

  58. Limaye, A. P. et al. Prospective assessment of cytomegalovirus immunity in high-risk donor-seropositive/recipient-seronegative liver transplant recipients receiving either preemptive therapy or antiviral prophylaxis. J. Infect. Dis. 220, 752–760 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Humar, A. et al. The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am. J Transpl. 10, 1228–1237 (2010).

    CAS  Google Scholar 

  60. Limaye, A. P. et al. Late-onset cytomegalovirus disease in liver transplant recipients despite antiviral prophylaxis. Transplantation 78, 1390–1396 (2004).

    PubMed  Google Scholar 

  61. Kotton, C. N. et al. The third international consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation 102, 900–931 (2018).

    PubMed  Google Scholar 

  62. Singh, N. et al. Effect of preemptive therapy vs antiviral prophylaxis on cytomegalovirus disease in seronegative liver transplant recipients with seropositive donors: a randomized clinical trial. JAMA 323, 1378–1387 (2020). This randomized study shows that PET significantly reduces late-onset disease compared with antiviral prophylaxis when used to manage patients with liver transplantation.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Emery, V. C., Cope, A. V., Bowen, E. F., Gor, D. & Griffiths, P. D. The dynamics of human cytomegalovirus replication in vivo. J. Exp. Med. 190, 177–182 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Emery, V. C., Hassan-Walker, A. F., Burroughs, A. K. & Griffiths, P. D. Human cytomegalovirus (HCMV) replication dynamics in HCMV-naive and -experienced immunocompromised hosts. J. Infect. Dis. 185, 1723–1728 (2002).

    PubMed  Google Scholar 

  65. Tong, Y., Pang, X. L., Mabilangan, C. & Preiksaitis, J. K. Determination of the biological form of human cytomegalovirus DNA in the plasma of solid-organ transplant recipients. J. Infect. Dis. 215, 1094–1101 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Razonable, R. R. et al. The clinical use of various blood compartments for cytomegalovirus (CMV) DNA quantitation in transplant recipients with CMV disease. Transplantation 73, 968–973 (2002).

    PubMed  Google Scholar 

  67. Hassan-Walker, A. F., Mattes, F. M., Griffiths, P. D. & Emery, V. C. Quantity of cytomegalovirus DNA in different leukocyte populations during active infection in vivo and the presence of gB and UL18 transcripts. J. Med. Virol. 64, 283–289 (2001).

    CAS  PubMed  Google Scholar 

  68. Van Damme, E. et al. Glucocorticosteroids trigger reactivation of human cytomegalovirus from latently infected myeloid cells and increase the risk for HCMV infection in D+R+ liver transplant patients. J. Gen. Virol. 96, 131–143 (2015).

    PubMed  PubMed Central  Google Scholar 

  69. Centers for Disease Control. Kaposi’s sarcoma and pneumocystis pneumonia among homosexual men — New York City and California. MMWR 30, 305–308 (1981).

    Google Scholar 

  70. Bowen, E. F. et al. Cytomegalovirus (CMV) viraemia detected by polymerase chain reaction identifies a group of HIV-positive patients at high risk of CMV disease. AIDS 11, 889–893 (1997).

    CAS  PubMed  Google Scholar 

  71. Bowen, E. F. et al. Natural history of untreated cytomegalovirus retinitis. Lancet 346, 1671–1673 (1995).

    CAS  PubMed  Google Scholar 

  72. Rubin, R. H. The indirect effects of cytomegalovirus infection on the outcome of organ transplantation. JAMA 261, 3607–3609 (1989). This editorial by an experienced infectious disease physician explains how HCMV is associated with indirect effects post transplantation.

    CAS  PubMed  Google Scholar 

  73. Vasilieva, E., Gianella, S. & Freeman, M. L. Novel strategies to combat CMV-related cardiovascular disease. Pathog. Immun. 5, 240–274 (2020).

    PubMed  PubMed Central  Google Scholar 

  74. Valantine, H. A. et al. Impact of prophylactic immediate posttransplant ganciclovir on development of transplant atherosclerosis: a post hoc analysis of a randomized, placebo-controlled study. Circulation 100, 61–66 (1999).

    CAS  PubMed  Google Scholar 

  75. Lowance, D. et al. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group. N. Engl. J. Med. 340, 1462–1470 (1999).

    CAS  PubMed  Google Scholar 

  76. Owers, D. S., Webster, A. C., Strippoli, G. F., Kable, K. & Hodson, E. M. Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients. Cochrane. Database. Syst. Rev. 2, CD005133 (2013).

    Google Scholar 

  77. Meyers, J. D. et al. Acyclovir for prevention of cytomegalovirus infection and disease after allogeneic marrow transplantation. N. Engl. J. Med. 318, 70–75 (1988).

    CAS  PubMed  Google Scholar 

  78. Prentice, H. G. et al. Impact of long-term acyclovir on cytomegalovirus infection and survival after allogeneic bone marrow transplantation. European Acyclovir for CMV Prophylaxis Study Group. Lancet 343, 749–753 (1994).

    CAS  PubMed  Google Scholar 

  79. Marty, F. M. et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N. Engl. J. Med. 377, 2433–2444 (2017).

    CAS  PubMed  Google Scholar 

  80. Ljungman, P. et al. A mortality analysis of letermovir prophylaxis for cytomegalovirus (CMV) in CMV-seropositive recipients of allogeneic hematopoietic-cell transplantation. Clin. Infect. Dis. 70, 1525–1533 (2019).

    PubMed Central  Google Scholar 

  81. Kempen, J. H. et al. Mortality risk for patients with cytomegalovirus retinitis and acquired immune deficiency syndrome. Clin. Infect. Dis. 37, 1365–1373 (2003).

    PubMed  Google Scholar 

  82. Ioannidis, J. P. et al. Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: a meta-analysis of randomized individual patient data. J. Infect. Dis. 178, 349–359 (1998).

    CAS  PubMed  Google Scholar 

  83. Griffiths, P. D. Studies of viral co-factors for human immunodeficiency virus in vitro and in vivo. J. Gen. Virol. 79, 213–220 (1998).

    CAS  PubMed  Google Scholar 

  84. Webster, A., McLaughlin, J. E., Johnson, M. A., Emery, V. C. & Griffiths, P. D. Use of the polymerase chain reaction to detect genomes of human immunodeficiency virus and cytomegalovirus in post-mortem tissues. J. Med. Virol. 47, 23–28 (1995).

    CAS  PubMed  Google Scholar 

  85. Hunt, P. W. et al. Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy. J. Infect. Dis. 203, 1474–1483 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Gianella, S. et al. Presence of asymptomatic cytomegalovirus and Epstein–Barr virus DNA in blood of persons with HIV starting antiretroviral therapy is associated with non-AIDS clinical events. AIDS 34, 849–857 (2020).

    CAS  PubMed  Google Scholar 

  87. Simanek, A. M. et al. Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States. PloS ONE 6, e16103 (2011). This article is the first large cohort study to examine and enumerate the excess mortality associated with HCMV in the general population.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Gkrania-Klotsas, E. et al. Seropositivity and higher immunoglobulin G antibody levels against cytomegalovirus are associated with mortality in the population-based European Prospective Investigation of Cancer — Norfolk cohort. Clin. Infect. Dis. 56, 1421–1427 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Limaye, A. P. et al. Effect of ganciclovir on IL-6 levels among cytomegalovirus-seropositive adults with critical illness: a randomized clinical trial. JAMA 318, 731–740 (2017).

    PubMed  PubMed Central  Google Scholar 

  90. Kadambari, S., Klenerman, P. & Pollard, A. J. Why the elderly appear to be more severely affected by COVID-19: the potential role of immunosenescence and CMV. Rev. Med. Virol. 30, e2144 (2020).

    CAS  PubMed  Google Scholar 

  91. Shrock, E. et al. Viral epitope profiling of COVID-19 patients reveals cross-reactivity and correlates of severity. Science 71, 2375–2385 (2020).

    Google Scholar 

  92. Kumar, D. et al. A prospective multicenter observational study of cell-mediated immunity as a predictor for cytomegalovirus infection in kidney transplant recipients. Am. J. Transpl. 19, 2505–2516 (2019).

    CAS  Google Scholar 

  93. Jarque, M. et al. Cellular immunity to predict the risk of cytomegalovirus infection in kidney transplantation: a prospective, interventional, multicenter clinical trial. Clin. Infect. Dis. 71, 2375–2385 (2020). This article is the first study to show convincingly that measures of cell-mediated immunity at baseline could predict future episodes of viraemia in individuals post transplant.

    CAS  PubMed  Google Scholar 

  94. Sylwester, A. W. et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J. Exp. Med. 202, 673–685 (2005). This extensive, comprehensive study shows that the immune system responds to the entire set of proteins encoded by HCMV.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Jackson, S. E., Mason, G. M., Okecha, G., Sissons, J. G. & Wills, M. R. Diverse specificities, phenotypes, and antiviral activities of cytomegalovirus-specific CD8+ T cells. J. Virol. 88, 10894–10908 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Jackson, S. E., Sedikides, G. X., Okecha, G. & Wills, M. R. Generation, maintenance and tissue distribution of T cell responses to human cytomegalovirus in lytic and latent infection. Med. Microbiol. Immunol. 208, 375–389 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Elkington, R. et al. Ex vivo profiling of CD8+-T-cell responses to human cytomegalovirus reveals broad and multispecific reactivities in healthy virus carriers. J. Virol. 77, 5226–5240 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Sylwester, A. et al. A new perspective of the structural complexity of HCMV-specific T-cell responses. Mech. Ageing Dev. 158, 14–22 (2016).

    CAS  PubMed  Google Scholar 

  99. Walter, E. A. et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N. Engl. J. Med. 333, 1038–1044 (1995). This article is the first demonstration that T cells specific for HCMV could safely be adoptively transferred in SCT.

    CAS  PubMed  Google Scholar 

  100. Vlahava, V. M. et al. Monoclonal antibodies targeting nonstructural viral antigens can activate ADCC against human cytomegalovirus. J. Clin. Invest. 131, https://doi.org/10.1172/JCI139296 (2021). This article is the first demonstration that antibody-dependent cellular toxicity is directed against the immune evasin proteins of HCMV rather than structural glycoproteins.

  101. Winston, D. J. et al. Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem-cell transplant recipients: a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study. Blood 111, 5403–5410 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Marty, F. M. et al. CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. N. Engl. J. Med. 369, 1227–1236 (2013).

    CAS  PubMed  Google Scholar 

  103. Chemaly, R. F. et al. Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation. N. Eng. J.Med. 370, 1781–1789 (2014).

    CAS  Google Scholar 

  104. Marty, F. M. et al. Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial. Lancet Infect.Dis. 11, 284–292 (2011).

    CAS  PubMed  Google Scholar 

  105. Marty, F. M. et al. A randomized, double-blind, placebo-controlled phase 3 trial of oral brincidofovir for cytomegalovirus prophylaxis in allogeneic hematopoietic cell transplantation. Biol. Blood Marrow Transpl. 25, 369–381 (2019).

    CAS  Google Scholar 

  106. Plotkin, S. A. et al. Towne-vaccine-induced prevention of cytomegalovirus disease after renal transplants. Lancet 1, 528–530 (1984).

    CAS  PubMed  Google Scholar 

  107. Griffiths, P. D. et al. Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial. Lancet 377, 1256–1263 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Baraniak, I. et al. Epitope-specific humoral responses to human cytomegalovirus glycoprotein-B vaccine with MF59: anti-AD2 levels correlate with protection from viremia. J. Infect. Dis. 217, 1907–1917 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Burke, H. G. & Heldwein, E. E. Crystal structure of the human cytomegalovirus glycoprotein B. PLoS Pathog. 11, e1005227 (2015).

    PubMed  PubMed Central  Google Scholar 

  110. Plotkin, S. A. Complex correlates of protection after vaccination. Clin. Infect. Dis. 56, 1458–1465 (2013).

    CAS  PubMed  Google Scholar 

  111. Ishida, J. H. et al. Phase 2 randomized, double-blind, placebo-controlled trial of RG7667, a combination monoclonal antibody, for prevention of cytomegalovirus infection in high-risk kidney transplant recipients. Antimicrob. Agents Chemother. 61, e01794–16 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Baraniak, I. A., Reeves, M. B. & Griffiths, P. D. Criteria to define interruption of transmission of human cytomegalovirus from organ donor to recipient. Rev. Med. Virol. 28, e1958 (2018).

    Google Scholar 

  113. Kharfan-Dabaja, M. A. et al. A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem-cell transplantation: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Infect. Dis. 12, 290–299 (2012).

    CAS  PubMed  Google Scholar 

  114. Schwendinger, M. et al. A randomized dose-escalating phase I trial of a replication-deficient lymphocytic choriomeningitis virus vector-based vaccine against human cytomegalovirus. J. Infect. Dis. https://doi.org/10.1093/infdis/jiaa121 (2020).

    Article  PubMed  Google Scholar 

  115. Liu, Y. et al. A replication-defective human cytomegalovirus vaccine elicits humoral immune responses analogous to those with natural infection. J. Virol. 93, e00747–19 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Griffiths, P. & Hughes, B. Choice of study populations for vaccines. J. Infect. Dis. 221, S128–S134 (2020).

    PubMed  PubMed Central  Google Scholar 

  117. Vutien, P. et al. Association of donor and recipient cytomegalovirus serostatus on graft and patient survival in liver transplant recipients. Liver Transpl. https://doi.org/10.1002/lt.26045 (2021).

    Article  PubMed  Google Scholar 

  118. Martinez-Martin, N. et al. An unbiased screen for human cytomegalovirus identifies neuropilin-2 as a central viral receptor. Cell 174, 1158–1171.e19 (2018).

    CAS  PubMed  Google Scholar 

  119. Murray, M. J., Peters, N. E. & Reeves, M. B. Navigating the Host Cell Response during Entry into Sites of Latent Cytomegalovirus Infection. Pathogens 7, 30 (2018).

    PubMed Central  Google Scholar 

  120. Nichols, W. G., Price, T. H., Gooley, T., Corey, L. & Boeckh, M. Transfusion-transmitted cytomegalovirus infection after receipt of leukoreduced blood products. Blood 101, 4195–4200 (2003).

    CAS  PubMed  Google Scholar 

  121. Ljungman, P., Hakki, M. & Boeckh, M. Cytomegalovirus in hematopoietic stem cell transplant recipients. Hematol. Oncol. Clin. North Am. 25, 151–169 (2011).

    PubMed  PubMed Central  Google Scholar 

  122. Spector, S. A., Wong, R., Hsia, K., Pilcher, M. & Stempien, M. J. Plasma cytomegalovirus (CMV) DNA load predicts CMV disease and survival in AIDS patients. J. Clin. Invest 101, 497–502 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Bowen, E. F. et al. Cytomegalovirus polymerase chain reaction viraemia in patients receiving ganciclovir maintenance therapy for retinitis. AIDS 12, 605–611 (1998).

    CAS  PubMed  Google Scholar 

  124. Paya, C. et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am. J. Transplant. 4, 611–620 (2004).

    CAS  PubMed  Google Scholar 

  125. Limaye, A. P., Corey, L., Koelle, D. M., Davis, C. L. & Boeckh, M. Emergence of ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ transplants. Lancet 356, 645–649 (2000).

    CAS  PubMed  Google Scholar 

  126. Papanicolaou, G. A. et al. Maribavir for refractory or resistant cytomegalovirus infections in hematopoietic-cell or solid-organ transplant recipients: a randomized, dose-ranging, double-blind, phase 2 study. Clin. Infect. Dis. 68, 1255–1264 (2019).

    CAS  PubMed  Google Scholar 

  127. Weller, T. H., Macauley, J. C., Craig, J. M. & Wirth, P. Isolation of intranuclear inclusion producing agents from infants with illnesses resembling cytomegalic inclusion disease. Proc. Soc. Exp. Biol. Med. 94, 4–12 (1957).

    PubMed  Google Scholar 

  128. Weller, T. H. The cytomegaloviruses: ubiquitous agents with protean clinical manifestations. I. N. Engl. J. Med. 285, 203–214 (1971).

    CAS  PubMed  Google Scholar 

  129. Weller, T. H. The cytomegaloviruses: ubiquitous agents with protean clinical manifestations. II. N. Engl. J. Med. 285, 267–274 (1971).

    CAS  PubMed  Google Scholar 

  130. Cha, T. A. et al. Human cytomegalovirus clinical isolates carry at least 19 genes not found in laboratory strains. J.Virol. 70, 78–83 (1996). This article is the first description of some laboratory-adapted HCMV strains having large deletions.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Revello, M. G. & Gerna, G. Human cytomegalovirus tropism for endothelial/epithelial cells: scientific background and clinical implications. Rev. Med. Virol. 20, 136–155 (2010).

    CAS  PubMed  Google Scholar 

  132. Nguyen, C. C. & Kamil, J. P. Pathogen at the gates: human cytomegalovirus entry and cell tropism. Viruses 10, 704 (2018).

    CAS  PubMed Central  Google Scholar 

  133. Wang, D. & Shenk, T. Human cytomegalovirus virion protein complex required for epithelial and endothelial cell tropism. Proc. Natl Acad. Sci. USA 102, 18153–18158 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Vanarsdall, A. L. et al. CD147 promotes entry of pentamer-expressing human cytomegalovirus into epithelial and endothelial cells. mBio 9, e00781–18 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. E, X. et al. OR14I1 is a receptor for the human cytomegalovirus pentameric complex and defines viral epithelial cell tropism. Proc. Natl Acad. Sci. USA 116, 7043–7052 (2019).

    PubMed  PubMed Central  Google Scholar 

  136. Stanton, R. J. et al. Reconstruction of the complete human cytomegalovirus genome in a BAC reveals RL13 to be a potent inhibitor of replication. J. Clin. Invest. 120, 3191–3208 (2010). This article shows that cloning of HCMV strain Merlin as a bacterial artificial chromosome allows simple manipulation of the genome and preservation without the selective pressures caused by propagation in cell cultures.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Sijmons, S. et al. High-throughput analysis of human cytomegalovirus genome diversity highlights the widespread occurrence of gene-disrupting mutations and pervasive recombination. J. Virol. 89, 7673–7695 (2015). This article shows that next-generation sequencing allows the full extent of genome variability to be documented in circulating strains.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Suarez, N. M. et al. Human cytomegalovirus genomes sequenced directly from clinical material: variation, multiple-strain infection, recombination, and gene loss. J. Infect. Dis. 220, 781–791 (2019). This article applies next-generation sequencing to strains found directly in clinical material.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Lassalle, F. et al. Islands of linkage in an ocean of pervasive recombination reveals two-speed evolution of human cytomegalovirus genomes. Virus Evol. 2, vew017 (2016).

    PubMed  PubMed Central  Google Scholar 

  140. Dolan, A. et al. Genetic content of wild-type human cytomegalovirus. J. Gen. Virol. 85, 1301–1312 (2004).

    CAS  PubMed  Google Scholar 

  141. Stern-Ginossar, N. et al. Decoding human cytomegalovirus. Science 338, 1088–1093 (2012).

    CAS  PubMed  Google Scholar 

  142. Dunn, W. et al. Functional profiling of a human cytomegalovirus genome. Proc. Natl Acad. Sci. USA 100, 14223–14228 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Chou, S. W. & Dennison, K. M. Analysis of interstrain variation in cytomegalovirus glycoprotein B sequences encoding neutralization-related epitopes. J. Infect. Dis. 163, 1229–1234 (1991).

    CAS  PubMed  Google Scholar 

  144. Nelson, C. S. et al. Intrahost dynamics of human cytomegalovirus variants acquired by seronegative glycoprotein B vaccinees. J. Virol. 93, e01695–18 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Wloch, M. K. et al. Safety and immunogenicity of a bivalent cytomegalovirus DNA vaccine in healthy adult subjects. J. Infect. Dis. 197, 1634–1642 (2008).

    CAS  PubMed  Google Scholar 

  146. Hage, E. et al. Characterization of human cytomegalovirus genome diversity in immunocompromised hosts by whole-genome sequencing directly from clinical specimens. J. Infect. Dis. 215, 1673–1683 (2017).

    CAS  PubMed  Google Scholar 

  147. Renzette, N. et al. Limits and patterns of cytomegalovirus genomic diversity in humans. Proc. Natl Acad. Sci. USA 112, E4120–E4128 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Suarez, N. M. et al. Whole-genome approach to assessing human cytomegalovirus dynamics in transplant patients undergoing antiviral therapy. Front. Cell Infect. Microbiol. 10, 267 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Quinnan, G. V. Jr. et al. Cytotoxic T cells in cytomegalovirus infection: HLA-restricted T-lymphocyte and non-T-lymphocyte cytotoxic responses correlate with recovery from cytomegalovirus infection in bone-marrow-transplant recipients. N. Engl. J. Med. 307, 7–13 (1982).

    PubMed  Google Scholar 

  150. Reusser, P., Riddell, S. R., Meyers, J. D. & Greenberg, P. D. Cytotoxic T lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease. Blood 78, 1373–1380 (1991).

    CAS  PubMed  Google Scholar 

  151. Lilleri, D. et al. Human cytomegalovirus-specific CD4+ and CD8+ T-cell reconstitution in adult allogeneic hematopoietic stem cell transplant recipients and immune control of viral infection. Haematologica 93, 248–256 (2008).

    PubMed  Google Scholar 

  152. Gabanti, E. et al. Human cytomegalovirus (HCMV)-specific CD4+ and CD8+ T cells are both required for prevention of HCMV disease in seropositive solid-organ transplant recipients. PLoS ONE 9, e106044 (2014).

    PubMed  PubMed Central  Google Scholar 

  153. Feuchtinger, T. et al. Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation. Blood 116, 4360–4367 (2010).

    CAS  PubMed  Google Scholar 

  154. Kaeuferle, T., Krauss, R., Blaeschke, F., Willier, S. & Feuchtinger, T. Strategies of adoptive T-cell transfer to treat refractory viral infections post allogeneic stem cell transplantation. J. Hematol. Oncol. 12, 13 (2019).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Work in the authors’ laboratory is funded by the Wellcome Trust (WT/204870/Z/16/Z), the Medical Research Council (MRC) (MR/RO21384/1) and the National Institute for Health Research (NIHR) (II-LB-1117-20001).

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  1. Institute for Immunity and Transplantation, University College London, London, UK

    Paul Griffiths & Matthew Reeves

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  1. Paul Griffiths
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  2. Matthew Reeves
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Both authors researched data for the article. P.G. wrote the first draft, which was revised by M.R. Both authors contributed substantially to the discussion of content, reviewed the text and edited to form the final manuscript.

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Correspondence to Paul Griffiths.

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Competing interests

Both authors are co-inventors (along with I. Baraniak) on UK patent application number 2020135.6 assigned to University College London (UCL), entitled ‘hCMV antibody and vaccine target’, that deals with a novel antigenic domain on HCMV glycoprotein B (gB). UCL received funds from Takeda pharmaceuticals to compensate for the time P.G. spent as a member of the end-point committee for a randomized clinical trial (RCT) of maribavir. The authors declare no other competing interests.

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Nature Reviews Microbiology thanks N. Lemmermann who co-reviewed with S. Becker, C. Naucler, R. Stanton and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Infectious mononucleosis

A syndrome of fever and malaise with an excess of lymphocytes in the blood, many of them atypical in form.

Owl’s eye inclusion bodies

Intranuclear inclusions seen in histopathological sections from organ biopsies with human cytomegalovirus (HCMV) infection.

Pneumonitis

Inflammation in the interstitial tissue of the lung rather than the airways.

Leukoviraemia

The presence of human cytomegalovirus (HCMV) within the bloodstream that is attached to white blood cells or within them.

Methylprednisolone

A potent steroid given in high doses intravenously to deplete lymphocytes capable of causing graft rejection.

Atherosclerosis

A chronic inflammatory condition with proliferation of cells and accumulation of lipid that tends to reduce blood flow through the vessel.

Pseudo-type formation

The formation of a virus particle that contains structural elements from more than one virus; a typical example ‘types’ as the virus that shares the same surface proteins.

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Griffiths, P., Reeves, M. Pathogenesis of human cytomegalovirus in the immunocompromised host. Nat Rev Microbiol 19, 759–773 (2021). https://doi.org/10.1038/s41579-021-00582-z

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