Encyclopedia of Gerontology and Population Aging

Living Edition
| Editors: Danan Gu, Matthew E. Dupre

Cytomegalovirus and Human Immune System Aging

  • Paul MossEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-69892-2_349-1

Definition

Cytomegalovirus (CMV) is a persistent viral infection that is present in most older people. Effective control of infection depends on a strong and sustained virus-specific immune response, and there is concern that this can weaken the ability to control other infections and may lead to immunopathology. Epidemiological studies have shown that infection does increase mortality risk in some populations, but this has not been seen consistently. We now need to understand the biological basis of these conflicting findings and to develop treatment approaches for older people at risk.

Overview

Cytomegalovirus is a member of the herpesvirus family, and chronic infection is widely prevalent in the human population (Reddehase 2006). Infection can be a major clinical problem for the fetus or in patients who are immunosuppressed, and there is now concern that it may also cause health problems in apparently healthy older people. In particular, a strong and sustained immune response is...

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

References

  1. Adriaensen W, Pawelec G, Vaes B, Hamprecht K, Derhovanessian E, van Pottelbergh G, Degryse JM, Matheï C (2017) CD4:8 ratio above 5 is associated with all-cause mortality in CMV-seronegative very old women: results from the BELFRAIL study. J Gerontol A Biol Sci Med Sci 72(9):1155–1162Google Scholar
  2. Bartlett DB, Firth CM, Phillips AC, Moss P, Baylis D, Syddall H, Sayer AA, Cooper C, Lord JM (2012) The age-related increase in low-grade systemic inflammation (inflammaging) is not driven by cytomegalovirus infection. Aging Cell 11(5):912–915CrossRefGoogle Scholar
  3. Beswick M, Pachnio A, Lauder SN, Sweet C, Moss PA (2013) Antiviral therapy can reverse the development of immune senescence in elderly mice with latent cytomegalovirus infection. J Virol 87(2):779–789CrossRefGoogle Scholar
  4. Bolovan-Fritts CA, Spector SA (2008) Endothelial damage from cytomegalovirus-specific host immune response can be prevented by targeted disruption of fractalkine-CX3CR1 interaction. Blood 111:175–182CrossRefGoogle Scholar
  5. Chanouzas D, Sagmeister M, Faustini S, Nightingale P, Richter A, Ferro CJ, Morgan MD, Moss P, Harper L (2019) Subclinical reactivation of cytomegalovirus drives CD4+CD28null T-cell expansion and impaired immune response to pneumococcal vaccination in antineutrophil cytoplasmic antibody–associated vasculitis. J Infect Dis 219(2):234–244CrossRefGoogle Scholar
  6. Cheng J, Ke Q, Jin Z, Wang H, Kocher O, Morgan JP, Zhang J, Crumpacker CS (2009) Cytomegalovirus infection causes an increase of arterial blood pressure. PLoS Pathog 5:e1000427CrossRefGoogle Scholar
  7. Chidrawar S, Khan N, Wei W, McLarnon A, Smith N, Nayak L, Moss P (2009) Cytomegalovirus-seropositivity has a profound influence on the magnitude of major lymphoid subsets within healthy individuals. Clin Exp Immunol 155(3):423–432CrossRefGoogle Scholar
  8. Costa-Garcia M, Vera A, Moraru M, Vilches C, López-Botet M, Muntasell A (2015) Antibody-mediated response of NKG2Cbright NK cells against human cytomegalovirus. J Immunol 194(6):2715–2724CrossRefGoogle Scholar
  9. Cudini J, Roy S, Houldcroft CJ, Bryant JM, Depledge DP, Tutill H, Veys P, Williams R, Worth AJJ, Tamuri AU, Goldstein RA, Breuer J (2019) Human cytomegalovirus haplotype reconstruction reveals high diversity due to superinfection and evidence of within-host recombination. Proc Natl Acad Sci USA 116:5693CrossRefGoogle Scholar
  10. den Elzen WP, Vossen AC, Cools HJ, Westendorp RG, Kroes AC, Gussekloo J (2011) Cytomegalovirus infection and responsiveness to influenza vaccination in elderly residents of long-term care facilities. Vaccine 29(29–30):4869–4874CrossRefGoogle Scholar
  11. Derhovanessian E, Maier AB, Hähnel K, Zelba H, de Craen AJ, Roelofs H, Slagboom EP, Westendorp RG, Pawelec G (2013) Lower proportion of naïve peripheral CD8+ T cells and an unopposed pro-inflammatory response to human cytomegalovirus proteins in vitro are associated with longer survival in very elderly people. Age (Dordr) 35(4):1387–1399CrossRefGoogle Scholar
  12. Firth C, Harrison R, Ritchie S, Wardlaw J, Ferro CJ, Starr JM, Deary IJ, Moss P (2016) Cytomegalovirus infection is associated with an increase in systolic blood pressure in older individuals. QJM 109(9):595–600CrossRefGoogle Scholar
  13. Furman D, Jojic V, Sharma S, Shen-Orr SS, Angel CJ, Onengut-Gumuscu S, Kidd BA, Maecker HT, Concannon P, Dekker CL, Thomas PG, Davis MM (2015) Cytomegalovirus infection enhances the immune response to influenza. Sci Transl Med 7(281):281ra43CrossRefGoogle Scholar
  14. Gillespie GM, Wills MR, Appay V, O’Callaghan C, Murphy M, Smith N, Sissons P, Rowland-Jones S, Bell JI, Moss PA (2000) Functional heterogeneity and high frequencies of cytomegalovirus-specific CD8(+) T lymphocytes in healthy seropositive donors. J Virol 74(17):8140–8150CrossRefGoogle Scholar
  15. Goldeck D, Larsen LA, Christiansen L, Christensen K, Hamprecht K, Pawelec G, Derhovanessian E (2016) Genetic influence on the peripheral blood CD4+ T-cell differentiation status in CMV infection. J Gerontol A Biol Sci Med Sci 71(12):1537–1543CrossRefGoogle Scholar
  16. Holder B, Miles DJ, Kaye S, Crozier S, Mohammed NI, Duah NO, Roberts E, Ojuola O, Palmero MS, Touray ES, Waight P, Cotten M, Rowland-Jones S, van der Sande M, Whittle H (2010) Epstein-Barr virus but not cytomegalovirus is associated with reduced vaccine antibody responses in Gambian infants. PLoS One 5(11):e14013CrossRefGoogle Scholar
  17. Jackson SE, Sedikides GX, Okecha G, Poole EL, Sinclair JH, Wills MR (2017) 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 8:733CrossRefGoogle Scholar
  18. Marandu TF, Oduro JD, Borkner L, Dekhtiarenko I, Uhrlaub JL, Drabig A, Kröger A, Nikolich-Zugich J, Cicin-Sain L (2015) Immune protection against virus challenge in aging mice is not affected by latent herpesviral infections. J Virol 89(22):11715–11717CrossRefGoogle Scholar
  19. Matheï C, Adriaensen W, Vaes B, Van Pottelbergh G, Wallemacq P, Degryse J (2015) No relation between CMV infection and mortality in the oldest old: results from the Belfrail study. Age Ageing 44(1):130–135CrossRefGoogle Scholar
  20. Miles DJC, Shumba F, Pachnio A, Begum J, Corbett EL, Heyderman RS, Moss P (2019) Early T cell differentiation with well-maintained function across the adult life course in Sub-Saharan Africa. J Immunol 203(5): 1160–1171CrossRefGoogle Scholar
  21. Misra MK, Mishra A, Pandey SK, Kapoor R, Sharma RK, Agrawal S (2015) Genetic variation in micro-RNA genes of host genome affects clinical manifestation of symptomatic human cytomegalovirus infection. Hum Immunol 76(10):765–769CrossRefGoogle Scholar
  22. Moss P (2019) ‘From immunosenescence to immune modulation’: a re-appraisal of the role of cytomegalovirus as major regulator of human immune function. Med Microbiol Immunol 208(3–4):271–280CrossRefGoogle Scholar
  23. Olsson J, Wikby A, Johansson B, Löfgren S, Nilsson BO, Ferguson FG (2000) Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study. Mech Ageing Dev 121(1–3): 187–201Google Scholar
  24. Pachnio A, Ciaurriz M, Begum J, Lal N, Zuo J, Beggs A, Moss P (2016) Cytomegalovirus infection leads to development of high frequencies of cytotoxic virus-specific CD4+ T cells targeted to vascular endothelium. PLoS Pathog 12(9):e1005832CrossRefGoogle Scholar
  25. Pera A, Campos C, Corona A, Sanchez-Correa B, Tarazona R, Larbi A, Solana R (2014) CMV latent infection improves CD8+ T response to SEB due to expansion of polyfunctional CD57+ cells in young individuals. PLoS One 9:e88538CrossRefGoogle Scholar
  26. Reddehase MJ (2006) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, NorfolkGoogle Scholar
  27. Redeker A, Remmerswaal EBM, van der Gracht ETI, Welten SPM, Höllt T, Koning F, Cicin-Sain L, Nikolich-Žugich J, Ten Berge IJM, van Lier RAW, van Unen V, Arens R (2018) The contribution of cytomegalovirus infection to immune senescence is set by the infectious dose. Front Immunol 8:1953CrossRefGoogle Scholar
  28. Roberts ET, Haan MN, Dowd JB, Aiello AE (2010) Cytomegalovirus antibody levels, inflammation, and mortality among elderly Latinos over 9 years of follow-up. Am J Epidemiol 172(4):363–371CrossRefGoogle Scholar
  29. Savva GM, Pachnio A, Kaul B, Morgan K, Huppert FA, Brayne C, Moss PA, Medical Research Council Cognitive Function and Ageing Study (2013) Cytomegalovirus infection is associated with increased mortality in the older population. Aging Cell 12(3):381–387CrossRefGoogle Scholar
  30. Simanek AM, Dowd JB, Pawelec G, Melzer D, Dutta A, Aiello AE (2011) Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States. PLoS One 6(2):e16103CrossRefGoogle Scholar
  31. Smith CJ, Turula H, Snyder CM (2014) Systemic hematogenous maintenance of memory inflation by MCMV infection. PLoS Pathog 10(7):e1004233CrossRefGoogle Scholar
  32. Strandberg TE, Pitkala KH, Tilvis RS (2009) Cytomegalovirus antibody level and mortality among community-dwelling older adults with stable cardiovascular disease. JAMA 301(4):380–382CrossRefGoogle Scholar
  33. Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F, Sleath PR, Grabstein KH, Hosken NA, Kern F et al (2005) Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med 202(5):673–685CrossRefGoogle Scholar
  34. Trzonkowski P, Mysliwska J, Szmit E, Wieckiewicz J, Lukaszuk K, Brydak LB, Machala M, Mysliwski A (2003) Association between cytomegalovirus infection, enhanced proinflammatory response and low level of antihemagglutinins during the anti-influenza vaccination – an impact of immunosenescence. Vaccine 21:3826–3836CrossRefGoogle Scholar
  35. van den Berg SPH, Wong A, Hendriks M, Jacobi RHJ, van Baarle D, van Beek J (2018) Negative effect of age, but not of latent Cytomegalovirus infection on the antibody response to a novel influenza vaccine strain in healthy adults. Front Immunol 9:82CrossRefGoogle Scholar
  36. Vescovini R, Biasini C, Fagnoni FF, Telera AR, Zanlari L, Pedrazzoni M, Bucci L, Monti D, Medici MC, Chezzi C et al (2007) Massive load of functional effector CD4+ and CD8+ T cells against cytomegalovirus in very old subjects. J Immunol 179(6):4283–4291CrossRefGoogle Scholar
  37. Vescovini R, Biasini C, Telera AR, Basaglia M, Stella A, Magalini F, Bucci L, Monti D, Lazzarotto T, Dal Monte P et al (2010) Intense antiextracellular adaptive immune response to human cytomegalovirus in very old subjects with impaired health and cognitive and functional status. J Immunol 184(6):3242–3249CrossRefGoogle Scholar
  38. Wall NA, Chue CD, Edwards NC, Pankhurst T, Harper L, Steeds RP, Lauder S, Townend JN, Moss P, Ferro CJ (2013) Cytomegalovirus seropositivity is associated with increased arterial stiffness in patients with chronic kidney disease. PLoS One 8(2):e55686CrossRefGoogle Scholar
  39. Wang GC, Kao WH, Murakami P, Xue QL, Chiou RB, Detrick B, McDyer JF, Semba RD, Casolaro V, Walston JD, Fried LP (2010) Cytomegalovirus infection and the risk of mortality and frailty in older women: a prospective observational cohort study. Am J Epidemiol 171(10):1144–1152CrossRefGoogle Scholar
  40. Weinberger B, Lazuardi L, Weiskirchner I, Keller M, Neuner C, Fischer KH, Neuman B, Würzner R, Grubeck-Loebenstein B (2007) Healthy aging and latent infection with CMV lead to distinct changes in CD8+ and CD4+ T-cell subsets in the elderly. Hum Immunol 68(2):86–90CrossRefGoogle Scholar
  41. Wikby A, Johansson B, Olsson J, Löfgren S, Nilsson BO, Ferguson F (2002) Expansions of peripheral blood CD8 T-lymphocyte subpopulations and an association with cytomegalovirus seropositivity in the elderly: the Swedish NONA immune study. Exp Gerontol 37(2–3):445–453CrossRefGoogle Scholar
  42. Yu HT, Youn JC, Kim JH, Seong YJ, Park SH, Kim HC, Lee WW, Park S, Shin EC (2017) Arterial stiffness is associated with cytomegalovirus-specific senescent CD8+ T cells. J Am Heart Assoc 6(9). pii: e006535.  https://doi.org/10.1161/JAHA.117.006535

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Institute of Immunology and ImmunotherapyUniversity of BirminghamBirminghamUK

Section editors and affiliations

  • Graham Pawelec
    • 1
    • 2
  1. 1.Department of ImmunologyUniversity of TübingenTübingenGermany
  2. 2.Health Sciences North Research InstituteSudburyCanada