Cytomegalovirus Infections in Humans

Abstract

Cytomegalovirus (CMV) is a herpes virus that causes severe disease in the immunocompromised because virus replication is normally held in check by cell‐mediated immune responses in patients with past infection. Patients receiving immunosuppressive drugs to allow allo‐transplantation, patients with AIDS (acquired immunodeficiency syndrome) or foetuses with immature immune responses are therefore at risk of developing CMV end‐organ disease. A high viral load is required for CMV end‐organ disease to develop. Ganciclovir is a potent inhibitor of CMV replication and can be used either for prophylaxis or for pre‐emptive therapy (administering the drug when CMV is detected in the blood). Both of these strategies effectively control CMV end‐organ disease in transplant patients. Three new drugs have recently completed phase II clinical trials (maribavir, brincidofovir and letermovir). Phase II studies of prototype CMV vaccines have recently published encouraging results, suggesting that CMV infection may ultimately be preventable by means of universal immunisation.

Key Concepts

  • CMV viraemia precedes CMV end‐organ disease.

  • Prompt treatment of CMV viraemia prevents end‐organ disease.

  • The probability of end‐organ disease is non‐linear with respect to viral load.

  • This threshold relationship is seen also in babies with congenital CMV infection and hearing loss.

  • Prompt treatment of congenital CMV infection can reduce the risk of progressive hearing loss.

  • Quantitative viraemia biomarkers can be used to assess the potency of antiviral drugs in humans.

  • These same biomarkers can be used to determine if vaccine given pre‐transplant can help control CMV replication post‐transplant.

  • Although clinically silent, CMV infection is associated with excess mortality in the general public.

  • Universal immunisation has the potential to provide health benefits greater than appreciated at present.

Keywords: cytomegalovirus; viral load; threshold; dynamics; indirect effects

Figure 1. Intracellular pathways leading to presentation of cytomegalovirus (CMV) peptide epitopes at the plasma membrane by HLA class I molecules. ER, endoplasmic reticulum; PM, plasma membrane; PRO, proteasome; RIB, ribosome; TAP, transporter associated with antigen presentation; TGN, ‐Golgi network and V, virus‐encoded protein. Letters and numbers indicate CMV proteins that can interfere with antigen presentation (as discussed in the text).
Figure 2. Probability of disease with increased augmented methylprednisolone: cumulative probability of symptomatic disease according to viral load and methylprednisolone usage (Cope ., ). Methylprednisolone usage: no drug given, purple line; one course, orange line; two courses, green line; three courses, red line and four courses, blue line. One course consists of 1 g a day for 3 days.
close

References

Bowen EF, Emery VC, Wilson P, et al. (1998) Cytomegalovirus polymerase chain reaction viraemia in patients receiving ganciclovir maintenance therapy for retinitis. AIDS 12: 605–611.

Cannon MJ and Davis KF (2005) Washing our hands of the congenital cytomegalovirus disease epidemic. BMC Public Health 5: 70.

Chemaly RF, Ullmann AJ, Stoelben S, et al. (2014) Letermovir for cytomegalovirus prophylaxis in hematopoietic‐cell transplantation. New England Journal of Medicine 370: 1781–1789.

Clinical Trials.gov Identifier ‐ NCT01753167. (2014) A Study of RG7667 for the Prevention of Cytomegalovirus Disease in Kidney Transplant Recipients. Online Source.

Cope AV, Sabin C, Burroughs A, et al. (1997a) 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. Journal of Infectious Diseases 176: 1484–1490.

Cope AV, Sweny P, Sabin C, et al. (1997b) Quantity of cytomegalovirus viruria is a major risk factor for cytomegalovirus disease after renal transplantation. Journal of Medical Virology 52: 200–205.

Deayton JR, Sabin CA, Johnson MA, et al. (2004) Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV‐infected patients receiving highly active antiretroviral therapy. Lancet 363: 2116–2121.

Emery VC, Cope AV, Bowen EF, et al. (1999) The dynamics of human cytomegalovirus replication in vivo. The Journal of Experimental Medicine 190: 177–182.

Emery VC, Sabin CA, Cope AV, et al. (2000) Application of viral‐load kinetics to identify patients who develop cytomegalovirus disease after transplantation. Lancet 355: 2032–2036.

Gkrania‐Klotsas E, Langenberg C, Sharp SJ, et al. (2013) Seropositivity and higher immunoglobulin g antibody levels against cytomegalovirus are associated with mortality in the population‐based European prospective investigation of Cancer‐Norfolk cohort. Clinical Infectious Diseases 56: 1421–1427.

Griffiths PD (2012) Burden of disease associated with human cytomegalovirus and prospects for elimination by universal immunisation. Lancet Infectious Diseases 12: 790–798.

Griffiths PD, McLean A and Emery VC (2001) Encouraging prospects for immunisation against primary cytomegalovirus infection. Vaccine 19: 1356–1362.

Griffiths PD, Stanton A, McCarrell E, et al. (2011) Cytomegalovirus glycoprotein‐B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo‐controlled trial. Lancet 377: 1256–1263.

Kempen JH, Jabs DA, Wilson LA, et al. (2003) Mortality risk for patients with cytomegalovirus retinitis and acquired immune deficiency syndrome. Clinical Infectious Diseases 37: 1365–1373.

Kharfan‐Dabaja MA, Boeckh M, Wilck MB, et al. (2012) A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem‐cell transplantation: a randomised, double‐blind, placebo‐controlled, phase 2 trial. Lancet Infectious Diseases 12: 290–299.

Kimberlin DW, Jester P, Sanchez PJ et al. (2013) Six months versus six weeks of oral valganciclovir for infants with symptomatic congenital cytomegalovirus (CMV) disease with and without central nervous system (CNS) involvement: results of a phase III, randomized, doubleblind, placebo‐controlled, multinational study. IDWeek 2013.

Kimberlin DW, Lin CY, Sanchez PJ, et al. (2003) Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. Journal of Pediatrics 143: 16–25.

Krause PR, Bialek SR, Boppana SB, et al. (2013) Priorities for CMV vaccine development. Vaccine 32: 4–10.

Lowance D, Neumayer HH, Legendre CM, et al. (1999) Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group. The New England Journal of Medicine 340: 1462–1470.

Marty FM and Boeckh M (2011) Maribavir and human cytomegalovirus‐what happened in the clinical trials and why might the drug have failed? Current Opinions in Virology 1: 555–562.

Marty FM, Ljungman P, Papanicolaou GA, et al. (2011) Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem‐cell transplants: a phase 3, double‐blind, placebo‐controlled, randomised trial. Lancet Infectious Diseases 11: 284–292.

Marty FM, Winston DJ, Rowley SD, et al. (2013) CMX001 to prevent cytomegalovirus disease in hematopoietic‐cell transplantation. The New England Journal of Medicine 369: 1227–1236.

Morton CC and Nance WE (2006) Newborn hearing screening – a silent revolution. The New England Journal of Medicine 354: 2151–2164.

Owers DS, Webster AC, Strippoli GF, et al. (2013) Pre‐emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Systematic Review 2: CD005133.

Pass RF, Zhang C, Evans A, et al. (2009) Vaccine prevention of maternal cytomegalovirus infection. The New England Journal of Medicine 360: 1191–1199.

Revello MG, Lazzarotto T, Guerra B, et al. (2014) A randomized trial of hyperimmune globulin to prevent congenital cytomegalovirus. The New England Journal of Medicine 370: 1316–1326.

Rubin RH (1989) The indirect effects of cytomegalovirus infection on the outcome of organ transplantation. Journal of the American Medical Association 261: 3607–3609.

Simanek AM, Dowd JB, Pawelec G, et al. (2011) Seropositivity to cytomegalovirus, inflammation, all‐cause and cardiovascular disease‐related mortality in the United States. PLoS One 6: e16103.

Spector SA, Hsia K, Crager M, et al. (1999) Cytomegalovirus (CMV) DNA load is an independent predictor of CMV disease and survival in advanced AIDS. Journal of Virology 73: 7027–7030.

Stagno S, Reynolds DW, Tsiantos A, et al. (1975) Comparative serial virologic and serologic studies of symptomatic and subclinical congenitally and natally acquired cytomegalovirus infections. Journal of Infectious Diseases 132: 568–577.

Stratton KR, Durch JS and Lawrence RS (2001) Vaccines for the 21st Century: A Tool for Decision Making. Washington, DC: National Academy Press.

Valantine HA, Gao SZ, Menon SG, et al. (1999) 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.

Walter S, Atkinson C, Sharland M, et al. (2008) Congenital cytomegalovirus: association between dried blood spot viral load and hearing loss. Archive of Disease in Childhood Fetal and Neonatal Edition 93: 280–285.

Winston DJ, Young JA, Pullarkat V, et al. (2008) 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.

Further Reading

Griffiths PD. The Stealth Virus. http://www.amazon.co.uk/Stealth‐Virus‐Prof‐Paul‐Griffiths/dp/1477566791/ref=pd_sim_b_1?ie=UTF8&refRID=1G62W6AHH51S2V0JF23X.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Griffiths, Paul D, and Lumley, Sheila(Jan 2015) Cytomegalovirus Infections in Humans. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002227.pub3]