1887

Abstract

The comparative long-term kinetics of human cytomegalovirus (HCMV) load and HCMV-specific antibody responses in the immunocompetent and immunocompromised solid-organ transplanted host during primary HCMV infection was investigated. In total, 40 immunocompetent subjects and 17 transplanted patients were examined for viral load as well as for IgG antibody responses to HCMV glycoproteins gH/gL/pUL128L, gH/gL and gB, and neutralizing antibodies in ARPE-19 epithelial cells and human fibroblasts. In parallel, the CD4 and CD8 HCMV-specific T-cell responses were determined by cytokine flow cytometry. Transplanted patients reached significantly higher viral DNA peaks, which persisted longer than in immunocompetent subjects. The ELISA-IgG responses to the pentamer, gH/gL and gB were significantly higher in primary infections of the immunocompetent until six months after onset, with the two antibody levels then overlapping from six to 12 months. Antibody levels neutralizing infection of epithelial cells were significantly higher in transplanted patients after six months, persisting for up to a year after transplantation. This trend was not observed for antibodies neutralizing infection of human fibroblasts, which showed higher titres in the immunocompetent over the entire one-year follow-up. In conclusion, in immunocompromised patients the viral load peak was much higher, while the neutralizing antibody response exceeded that detected in the immunocompetent host starting six months after onset of follow-up, often concomitantly with a lack of specific CD4 T cells. In this setting, the elevated antibody response occurred in the presence of differentiated follicular helper T cells in the blood, which decreased in number as did antibody titres upon reappearance of HCMV-specific CD4 T cells.

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2015-02-01
2019-11-20
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References

  1. Cui X., Meza B. P., Adler S. P., McVoy M. A.. ( 2008;). Cytomegalovirus vaccines fail to induce epithelial entry neutralizing antibodies comparable to natural infection. . Vaccine 26:, 5760–5766. [CrossRef][PubMed]
    [Google Scholar]
  2. Fouts A. E., Chan P., Stephan J. P., Vandlen R., Feierbach B.. ( 2012;). Antibodies against the gH/gL/UL128/UL130/UL131 complex comprise the majority of the anti-cytomegalovirus (anti-CMV) neutralizing antibody response in CMV hyperimmune globulin. . J Virol 86:, 7444–7447. [CrossRef][PubMed]
    [Google Scholar]
  3. Furione M., Rognoni V., Cabano E., Baldanti F.. ( 2012;). Kinetics of human cytomegalovirus (HCMV) DNAemia in transplanted patients expressed in international units as determined with the Abbott RealTime CMV assay and an in-house assay. . J Clin Virol 55:, 317–322. [CrossRef][PubMed]
    [Google Scholar]
  4. Furione M., Rognoni V., Sarasini A., Zavattoni M., Lilleri D., Gerna G., Revello M. G.. ( 2013;). Slow increase in IgG avidity correlates with prevention of human cytomegalovirus transmission to the fetus. . J Med Virol 85:, 1960–1967. [CrossRef][PubMed]
    [Google Scholar]
  5. Genini E., Percivalle E., Sarasini A., Revello M. G., Baldanti F., Gerna G.. ( 2011;). Serum antibody response to the gH/gL/pUL128-131 five-protein complex of human cytomegalovirus (HCMV) in primary and reactivated HCMV infections. . J Clin Virol 52:, 113–118. [CrossRef][PubMed]
    [Google Scholar]
  6. Gerna G., Percivalle E., Lilleri D., Lozza L., Fornara C., Hahn G., Baldanti F., Revello M. G.. ( 2005;). Dendritic-cell infection by human cytomegalovirus is restricted to strains carrying functional UL131-128 genes and mediates efficient viral antigen presentation to CD8+ T cells. . J Gen Virol 86:, 275–284. [CrossRef][PubMed]
    [Google Scholar]
  7. Gerna G., Vitulo P., Rovida F., Lilleri D., Pellegrini C., Oggionni T., Campanini G., Baldanti F., Revello M. G.. ( 2006;). Impact of human metapneumovirus and human cytomegalovirus versus other respiratory viruses on the lower respiratory tract infections of lung transplant recipients. . J Med Virol 78:, 408–416. [CrossRef][PubMed]
    [Google Scholar]
  8. Gerna G., Sarasini A., Patrone M., Percivalle E., Fiorina L., Campanini G., Gallina A., Baldanti F., Revello M. G.. ( 2008;). Human cytomegalovirus serum neutralizing antibodies block virus infection of endothelial/epithelial cells, but not fibroblasts, early during primary infection. . J Gen Virol 89:, 853–865. [CrossRef][PubMed]
    [Google Scholar]
  9. Griffiths P. D., Stanton A., McCarrell E., Smith C., Osman M., Harber M., Davenport A., Jones G., Wheeler D. C.. & other authors ( 2011;). Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial. . Lancet 377:, 1256–1263. [CrossRef][PubMed]
    [Google Scholar]
  10. Hahn G., Revello M. G., Patrone M., Percivalle E., Campanini G., Sarasini A., Wagner M., Gallina A., Milanesi G.. & other authors ( 2004;). Human cytomegalovirus UL131-128 genes are indispensable for virus growth in endothelial cells and virus transfer to leukocytes. . J Virol 78:, 10023–10033. [CrossRef][PubMed]
    [Google Scholar]
  11. He J., Tsai L. M., Leong Y. A., Hu X., Ma C. S., Chevalier N., Sun X., Vandenberg K., Rockman S.. & other authors ( 2013;). Circulating precursor CCR7loPD-1hi CXCR5+ CD4+ T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. . Immunity 39:, 770–781. [CrossRef][PubMed]
    [Google Scholar]
  12. Lilleri D., Zelini P., Fornara C., Comolli G., Revello M. G., Gerna G.. ( 2009;). Human cytomegalovirus-specific CD4+ and CD8+ T cell responses in primary infection of the immunocompetent and the immunocompromised host. . Clin Immunol 131:, 395–403. [CrossRef][PubMed]
    [Google Scholar]
  13. Lilleri D., Kabanova A., Lanzavecchia A., Gerna G.. ( 2012;). Antibodies against neutralization epitopes of human cytomegalovirus gH/gL/pUL128-130-131 complex and virus spreading may correlate with virus control in vivo. . J Clin Immunol 32:, 1324–1331. [CrossRef][PubMed]
    [Google Scholar]
  14. Lilleri D., Kabanova A., Revello M. G., Percivalle E., Sarasini A., Genini E., Sallusto F., Lanzavecchia A., Corti D., Gerna G.. ( 2013;). Fetal human cytomegalovirus transmission correlates with delayed maternal antibodies to gH/gL/pUL128-130-131 complex during primary infection. . PLoS ONE 8:, e59863. [CrossRef][PubMed]
    [Google Scholar]
  15. Lozza L., Lilleri D., Percivalle E., Fornara C., Comolli G., Revello M. G., Gerna G.. ( 2005;). Simultaneous quantification of human cytomegalovirus (HCMV)-specific CD4+ and CD8+ T cells by a novel method using monocyte-derived HCMV-infected immature dendritic cells. . Eur J Immunol 35:, 1795–1804. [CrossRef][PubMed]
    [Google Scholar]
  16. Macagno A., Bernasconi N. L., Vanzetta F., Dander E., Sarasini A., Revello M. G., Gerna G., Sallusto F., Lanzavecchia A.. ( 2010;). Isolation of human monoclonal antibodies that potently neutralize human cytomegalovirus infection by targeting different epitopes on the gH/gL/UL128-131A complex. . J Virol 84:, 1005–1013. [CrossRef][PubMed]
    [Google Scholar]
  17. Pass R. F., Zhang C., Evans A., Simpson T., Andrews W., Huang M. L., Corey L., Hill J., Davis E.. & other authors ( 2009;). Vaccine prevention of maternal cytomegalovirus infection. . N Engl J Med 360:, 1191–1199. [CrossRef][PubMed]
    [Google Scholar]
  18. Pötzsch S., Spindler N., Wiegers A. K., Fisch T., Rücker P., Sticht H., Grieb N., Baroti T., Weisel F.. & other authors ( 2011;). B cell repertoire analysis identifies new antigenic domains on glycoprotein B of human cytomegalovirus which are target of neutralizing antibodies. . PLoS Pathog 7:, e1002172. [CrossRef][PubMed]
    [Google Scholar]
  19. Revello M. G., Gerna G.. ( 2002;). Diagnosis and management of human cytomegalovirus infection in the mother, fetus, and newborn infant. . Clin Microbiol Rev 15:, 680–715. [CrossRef][PubMed]
    [Google Scholar]
  20. Revello M. G., Gerna G.. ( 2010;). Human cytomegalovirus tropism for endothelial/epithelial cells: scientific background and clinical implications. . Rev Med Virol 20:, 136–155. [CrossRef][PubMed]
    [Google Scholar]
  21. Revello M. G., Genini E., Gorini G., Klersy C., Piralla A., Gerna G.. ( 2010;). Comparative evaluation of eight commercial human cytomegalovirus IgG avidity assays. . J Clin Virol 48:, 255–259. [CrossRef][PubMed]
    [Google Scholar]
  22. Revello M. G., Fabbri E., Furione M., Zavattoni M., Lilleri D., Tassis B., Quarenghi A., Cena C., Arossa A.. & other authors ( 2011;). Role of prenatal diagnosis and counseling in the management of 735 pregnancies complicated by primary human cytomegalovirus infection: a 20-year experience. . J Clin Virol 50:, 303–307. [CrossRef][PubMed]
    [Google Scholar]
  23. Ryckman B. J., Rainish B. L., Chase M. C., Borton J. A., Nelson J. A., Jarvis M. A., Johnson D. C.. ( 2008;). Characterization of the human cytomegalovirus gH/gL/UL128-131 complex that mediates entry into epithelial and endothelial cells. . J Virol 82:, 60–70. [CrossRef][PubMed]
    [Google Scholar]
  24. Sallusto F., Lanzavecchia A.. ( 1994;). Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. . J Exp Med 179:, 1109–1118. [CrossRef][PubMed]
    [Google Scholar]
  25. Wang D., Shenk T.. ( 2005;). Human cytomegalovirus virion protein complex required for epithelial and endothelial cell tropism. . Proc Natl Acad Sci U S A 102:, 18153–18158. [CrossRef][PubMed]
    [Google Scholar]
  26. Zhou M., Yu Q., Wechsler A., Ryckman B. J.. ( 2013;). Comparative analysis of gO isoforms reveals that strains of human cytomegalovirus differ in the ratio of gH/gL/gO and gH/gL/UL128-131 in the virion envelope. . J Virol 87:, 9680–9690. [CrossRef][PubMed]
    [Google Scholar]
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