1887

Abstract

Human cytomegalovirus (CMV) establishes persistent, usually asymptomatic, infection in healthy people. Because CMV infection is associated with the presence of lower proportions of peripheral naïve CD8 T-cells and a higher fraction of late-differentiated CD8 cells, commonly taken as biomarkers of age-associated compromised adaptive immunity (‘immunosenescence’), we asked whether chronic exposure to any persistent virus mediates these effects. Herpes simplex virus (HSV) is also a widespread herpesvirus that establishes lifelong persistence, but, unlike CMV, its impact on the distribution of T-cell subsets has not been established. Here, we analysed T-cell subsets in 93 healthy people aged 42–81 years infected or not infected with CMV and/or HSV. Individuals harbouring CMV were confirmed to possess lower frequencies of naïve CD8 T-cells (defined as CD45RACCR7CD27CD28) and greater proportions of late-differentiated effector memory (CD45RACCR7CD27CD28) and so-called TEMRA (CD45RACCR7CD27CD28) CD4 and CD8 subsets, independent of HSV seropositivity. In CMV-seronegative donors, HSV did not affect T-cell subset distribution significantly. We conclude that these hallmarks of age-associated alterations to immune signatures are indeed observed in the general population in people infected with CMV and not those infected with a different persistent herpesvirus.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.036004-0
2011-12-01
2020-05-26
Loading full text...

Full text loading...

/deliver/fulltext/jgv/92/12/2746.html?itemId=/content/journal/jgv/10.1099/vir.0.036004-0&mimeType=html&fmt=ahah

References

  1. Allan R. S., Smith C. M., Belz G. T., van Lint A. L., Wakim L. M., Heath W. R., Carbone F. R. 2003; Epidermal viral immunity induced by CD8α+ dendritic cells but not by Langerhans cells. Science 301:1925–1928 [CrossRef][PubMed]
    [Google Scholar]
  2. Almanzar G., Schwaiger S., Jenewein B., Keller M., Herndler-Brandstetter D., Würzner R., Schönitzer D., Grubeck-Loebenstein B. 2005; Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8+ T-cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons. J Virol 79:3675–3683 [CrossRef][PubMed]
    [Google Scholar]
  3. Appay V., Dunbar P. R., Callan M., Klenerman P., Gillespie G. M., Papagno L., Ogg G. S., King A., Lechner F. et al. other authors 2002; Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med 8:379–385 [CrossRef][PubMed]
    [Google Scholar]
  4. Bosnjak L., Miranda-Saksena M., Koelle D. M., Boadle R. A., Jones C. A., Cunningham A. L. 2005; Herpes simplex virus infection of human dendritic cells induces apoptosis and allows cross-presentation via uninfected dendritic cells. J Immunol 174:2220–2227[PubMed] [CrossRef]
    [Google Scholar]
  5. 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 155:423–432 [CrossRef][PubMed]
    [Google Scholar]
  6. Colonna-Romano G., Akbar A. N., Aquino A., Bulati M., Candore G., Lio D., Ammatuna P., Fletcher J. M., Caruso C., Pawelec G. 2007; Impact of CMV and EBV seropositivity on CD8 T lymphocytes in an old population from West-Sicily. Exp Gerontol 42:995–1002 [CrossRef][PubMed]
    [Google Scholar]
  7. Crough T., Khanna R. 2009; Immunobiology of human cytomegalovirus: from bench to bedside. Clin Microbiol Rev 22:76–98 [CrossRef][PubMed]
    [Google Scholar]
  8. Cunningham A. L., Diefenbach R. J., Miranda-Saksena M., Bosnjak L., Kim M., Jones C., Douglas M. W. 2006; The cycle of human herpes simplex virus infection: virus transport and immune control. J Infect Dis 194:Suppl. 1S11–S18 [CrossRef][PubMed]
    [Google Scholar]
  9. Derhovanessian E., Larbi A., Pawelec G. 2009; Biomarkers of human immunosenescence: impact of cytomegalovirus infection. Curr Opin Immunol 21:440–445 [CrossRef][PubMed]
    [Google Scholar]
  10. Derhovanessian E., Maier A. B., Beck R., Jahn G., Hähnel K., Slagboom P. E., de Craen A. J., Westendorp R. G., Pawelec G. 2010; Hallmark features of immunosenescence are absent in familial longevity. J Immunol 185:4618–4624 [CrossRef][PubMed]
    [Google Scholar]
  11. Fletcher J. M., Vukmanovic-Stejic M., Dunne P. J., Birch K. E., Cook J. E., Jackson S. E., Salmon M., Rustin M. H., Akbar A. N. 2005; Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion. J Immunol 175:8218–8225[PubMed] [CrossRef]
    [Google Scholar]
  12. Khan N., Shariff N., Cobbold M., Bruton R., Ainsworth J. A., Sinclair A. J., Nayak L., Moss P. A. 2002; Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J Immunol 169:1984–1992[PubMed] [CrossRef]
    [Google Scholar]
  13. Khan N., Hislop A., Gudgeon N., Cobbold M., Khanna R., Nayak L., Rickinson A. B., Moss P. A. 2004; Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. J Immunol 173:7481–7489[PubMed] [CrossRef]
    [Google Scholar]
  14. Koch S., Larbi A., Derhovanessian E., Ozcelik D., Naumova E., Pawelec G. 2008; Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people. Immun Ageing 5:6 [CrossRef][PubMed]
    [Google Scholar]
  15. Lang A., Brien J. D., Nikolich-Zugich J. 2009; Inflation and long-term maintenance of CD8 T cells responding to a latent herpesvirus depend upon establishment of latency and presence of viral antigens. J Immunol 183:8077–8087 [CrossRef][PubMed]
    [Google Scholar]
  16. Looney R. J., Falsey A., Campbell D., Torres A., Kolassa J., Brower C., McCann R., Menegus M., McCormick K. et al. other authors 1999; Role of cytomegalovirus in the T cell changes seen in elderly individuals. Clin Immunol 90:213–219 [CrossRef][PubMed]
    [Google Scholar]
  17. Mark K. E., Wald A., Magaret A. S., Selke S., Olin L., Huang M. L., Corey L. 2008; Rapidly cleared episodes of herpes simplex virus reactivation in immunocompetent adults. J Infect Dis 198:1141–1149 [CrossRef][PubMed]
    [Google Scholar]
  18. Ouyang Q., Wagner W. M., Walter S., Müller C. A., Wikby A., Aubert G., Klatt T., Stevanovic S., Dodi T., Pawelec G. 2003; An age-related increase in the number of CD8+ T cells carrying receptors for an immunodominant Epstein–Barr virus (EBV) epitope is counteracted by a decreased frequency of their antigen-specific responsiveness. Mech Ageing Dev 124:477–485 [CrossRef][PubMed]
    [Google Scholar]
  19. Pawelec G., Derhovanessian E., Larbi A., Strindhall J., Wikby A. 2009; Cytomegalovirus and human immunosenescence. Rev Med Virol 19:47–56 [CrossRef][PubMed]
    [Google Scholar]
  20. Pourgheysari B., Khan N., Best D., Bruton R., Nayak L., Moss P. A. 2007; The cytomegalovirus-specific CD4+ T-cell response expands with age and markedly alters the CD4+ T-cell repertoire. J Virol 81:7759–7765 [CrossRef][PubMed]
    [Google Scholar]
  21. Romero P., Zippelius A., Kurth I., Pittet M. J., Touvrey C., Iancu E. M., Corthesy P., Devevre E., Speiser D. E., Rufer N. 2007; Four functionally distinct populations of human effector-memory CD8+ T lymphocytes. J Immunol 178:4112–4119[PubMed] [CrossRef]
    [Google Scholar]
  22. Schoenmaker M., de Craen A. J., de Meijer P. H., Beekman M., Blauw G. J., Slagboom P. E., Westendorp R. G. 2006; Evidence of genetic enrichment for exceptional survival using a family approach: the Leiden Longevity Study. Eur J Hum Genet 14:79–84[PubMed]
    [Google Scholar]
  23. Sester M., Sester U., Gärtner B., Kubuschok B., Girndt M., Meyerhans A., Köhler H. 2002; Sustained high frequencies of specific CD4 T cells restricted to a single persistent virus. J Virol 76:3748–3755 [CrossRef][PubMed]
    [Google Scholar]
  24. Siegal F. P., Lopez C., Hammer G. S., Brown A. E., Kornfeld S. J., Gold J., Hassett J., Hirschman S. Z., Cunningham-Rundles C. et al. other authors 1981; Severe acquired immunodeficiency in male homosexuals, manifested by chronic perianal ulcerative herpes simplex lesions. N Engl J Med 305:1439–1444 [CrossRef][PubMed]
    [Google Scholar]
  25. Smith J. S., Robinson N. J. 2002; Age-specific prevalence of infection with herpes simplex virus types 2 and 1: a global review. J Infect Dis 186:Suppl. 1S3–S28 [CrossRef][PubMed]
    [Google Scholar]
  26. Sylwester A. W., Mitchell B. L., Edgar J. B., Taormina C., Pelte C., Ruchti F., Sleath P. R., Grabstein K. H., Hosken N. A. et al. other authors 2005; Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med 202:673–685 [CrossRef][PubMed]
    [Google Scholar]
  27. Vescovini R., Telera A., Fagnoni F. F., Biasini C., Medici M. C., Valcavi P., di Pede P., Lucchini G., Zanlari L. et al. other authors 2004; Different contribution of EBV and CMV infections in very long-term carriers to age-related alterations of CD8+ T cells. Exp Gerontol 39:1233–1243 [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.036004-0
Loading
/content/journal/jgv/10.1099/vir.0.036004-0
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error