Early Post-Transplant Torquetenovirus Viremia Predicts Cytomegalovirus Reactivations In Solid Organ Transplant Recipients

Fabrizio Maggi, Daniele Focosi, Maura Statzu, Gabriele Bianco, Cristina Costa, Lisa Macera, Pietro Giorgio Spezia, Chiara Medici, Eliseo Albert, David Navarro, Carolina Scagnolari, Mauro Pistello, Rossana Cavallo, Guido Antonelli, Fabrizio Maggi, Daniele Focosi, Maura Statzu, Gabriele Bianco, Cristina Costa, Lisa Macera, Pietro Giorgio Spezia, Chiara Medici, Eliseo Albert, David Navarro, Carolina Scagnolari, Mauro Pistello, Rossana Cavallo, Guido Antonelli

Abstract

Monitoring the human virome has been recently suggested as a promising and novel area of research for identifying new biomarkers which would help physicians in the management of transplant patients. Imbalance of the immune system in transplant recipients has a significant impact on replication of Torquetenovirus (TTV), the most representative and abundant virus of human virome. TTV kinetic was studied by real-time PCR in 280 liver or kidney transplant recipients who underwent different drug regimens to maintain immunosuppression. During one-year post-transplant follow-up, TTV viremia fluctuated irrespective of transplanted organ type but consistent with the immunosuppression regimen. TTV kinetic in patients who manifested cytomegalovirus (CMV) reactivation within the first four months post-transplant differed from that observed in patients who did not experience CMV complications. Importantly, plasma TTV load measured between day 0 and 10 post-transplant was significantly higher in CMV DNA positive than in CMV DNA negative patients. TTV viremia above 3.45 log DNA copies/ml within the first 10 days post-transplant correlates with higher propensity to CMV reactivation following transplantation. This study provides further evidence for using early post-transplant TTV viremia to predict CMV reactivation in liver or kidney transplant recipients.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
TTV DNA loads in plasma specimens of all study transplant recipients monitored for one year post-transplant and grouped according to their CMV DNA status as measured in the first four months post-transplant.
Figure 2
Figure 2
Comparison of TTV levels in all study transplant recipients monitored between 0 and 10 days post-transplant and grouped according to their CMV DNA status as measured in the first four months post-transplant.
Figure 3
Figure 3
Comparison of TTV levels in liver and kidney transplant recipients monitored between 0 and 10 days post-transplant and grouped according to their CMV DNA status as measured in the first four months post-transplant.
Figure 4
Figure 4
Receiver operating characteristic (ROC) curve for distinguishing the optimal cutoff value for TTV load.

References

    1. Stegall MD, Morris RE, Alloway RR, Mannon RB. Developing New immunosuppression for the next generation of transplant recipients: the path forward. Am. J. Transplant. 2016;16:1094–1101. doi: 10.1111/ajt.13582.
    1. Haidar G, Singh N. Viral infections in solid organ transplant recipients: novel updates and a review of the classics. Curr. Opin. Infect. Dis. 2017;30:579–588. doi: 10.1097/QCO.0000000000000409.
    1. Salvadori M, Tsalouchos A. Biomarkers in renal transplantation: An updated review. World. J. Transplant. 2017;7:161–178. doi: 10.5500/wjt.v7.i3.161.
    1. Lee H, et al. Cytomegalovirus (CMV) immune monitoring with ELISPOT and QuantiFERON-CMV assay in seropositive kidney transplant recipients. PLoS One. 2017;12:e0189488. doi: 10.1371/journal.pone.0189488.
    1. Kaminski H, et al. Surveillance of γδ T cells predicts cytomegalovirus infection resolution in kidney transplants. J. Am. Soc. Nephrol. 2016;27:637–645. doi: 10.1681/ASN.2014100985.
    1. Nishizawa T, et al. A novel DNAvirus (TTV) associated with elevated transaminase levels in posttransfusion hepatitis of unknown etiology. Biochem . Biophys. Res. Commun. 1997;241:92–97. doi: 10.1006/bbrc.1997.7765.
    1. Biagini P. Classification of TTV and related viruses (anelloviruses) Curr. Top. Microbiol. Immunol. 2009;331:21–33.
    1. Bendinelli M, et al. Molecular properties, biology, and clinical implications of TT virus, a recently identified widespread infectious agent of human. Clin. Microbiol. Rev. 2001;14:98–113. doi: 10.1128/CMR.14.1.98-113.2001.
    1. Maggi F, et al. Blood levels of TT virus following immune stimulation with influenza or hepatitis B vaccine. J. Med. Virol. 2005;75:358–365. doi: 10.1002/jmv.20278.
    1. De Vlaminck I, et al. Temporal response of the human virome to immunosuppression and antiviral therapy. Cell. 2013;155:1178–1187. doi: 10.1016/j.cell.2013.10.034.
    1. Ling L, et al. AIDS alters the commensal plasma virome. J. Virol. 2013;87:10912–10915. doi: 10.1128/JVI.01839-13.
    1. Masouridi-Levrat S, et al. Torque teno virus in patients undergoing allogeneic hematopoietic stem cell transplantation for hematological malignancies. Bone Marrow Transplant. 2016;51:440–442. doi: 10.1038/bmt.2015.262.
    1. Pistello M, et al. TT virus levels in the plasma of infected individuals with different hepatic and extrahepatic pathology. J. Med. Virol. 2001;63:189–195. doi: 10.1002/1096-9071(20000201)63:2<189::AID-JMV1014>;2-H.
    1. Maggi F, et al. Dynamics of persistent TT virus infection, as determined in patients treated with alpha interferon for concomitant hepatitis C virus infection. J. Virol. 2001;75:11999–12004. doi: 10.1128/JVI.75.24.11999-12004.2001.
    1. Virgin HW, Wherry EJ, Ahmed R. Redefining chronic viral infection. Cell. 2009;138:30–50. doi: 10.1016/j.cell.2009.06.036.
    1. Carding SR, Davis N, Hoyles L. The human intestinal virome in health and disease. Aliment. Pharmacol. Ther. 2017;46:800–815. doi: 10.1111/apt.14280.
    1. Legoff J, et al. The eukaryotic gut virome in hematopoietic stem cell transplantation: new clues in enteric graft-versus-host disease. Nat. Med. 2017;23:1080–10875. doi: 10.1038/nm.4380.
    1. Barzon L, Lavezzo E, Militello V, Toppo S, Palù G. Applications of next-generation sequencing technologies to diagnostic virology. Int. J. Mol. Sci. 2011;12:7861–7884. doi: 10.3390/ijms12117861.
    1. Maggi F, Bendinelli M. Immunobiology of the torque teno viruses and other anelloviruses. Curr. Top. Microbiol. Immunol. 2009;331:65–90.
    1. Béland K, et al. Torque teno virus in children who underwent orthotopic liver transplantation: new insights about a common pathogen. J. Infect. Dis. 2014;209:247–254. doi: 10.1093/infdis/jit423.
    1. Li L, et al. Virome analysis of antiretroviral-treated HIV patients shows no correlation between T-cell activation and anelloviruses levels. J. Clin. Virol. 2015;72:106–113. doi: 10.1016/j.jcv.2015.09.004.
    1. McElvania TeKippe E, et al. Increased prevalence of anellovirus in pediatric patients with fever. PLoS One. 2012;7:e50937. doi: 10.1371/journal.pone.0050937.
    1. Young JC, Chehoud C, Bittinger K. Viral metagenomics reveal blooms of anelloviruses in the respiratory tract of lung transplant recipients. Am. J. Transplant. 2015;15:200–209. doi: 10.1111/ajt.13031.
    1. Görzer I, Haloschan M, Jaksch P, Klepetko W, Puchhammer-Stöckl E. Plasma DNA levels of torque teno virus and immunosuppression after lung transplantation. J. Heart. Lung Transplant. 2014;33:320–323. doi: 10.1016/j.healun.2013.12.007.
    1. Focosi D, Macera L, Boggi U, Ceccherini Nelli L, Maggi F. Short-term kinetics of torque teno virus viraemia after induction immunosuppression confirm T lymphocytes as the main replication-competent cells. J. Gen. Virol. 2015;96:115–117. doi: 10.1099/vir.0.070094-0.
    1. Focosi D, Macera L, Pistello M, Maggi F. Torque teno virus viremia correlates with intensity of maintenance immunosuppression in adult orthotopic liver transplant. J. Infect. Dis. 2014;210:667–668. doi: 10.1093/infdis/jiu209.
    1. Iwasaki K. Metabolism of Tacrolimus (FK506) and recent topics in clinical pharmacokinetics. Drug Metab. Pharmacokinet. 2007;22:328–335. doi: 10.2133/dmpk.22.328.
    1. Görzer I, Jaksch P, Strassl R, Klepetko W, Puchhammer-Stöckl E. Association between plasma Torque teno virus level and chronic lung allograft dysfunction after lung transplantation. J. Heart Lung Transplant. 2017;36:366–368. doi: 10.1016/j.healun.2016.10.011.
    1. Béland K, et al. Torque teno virus load as a biomarker of immunosuppression? New hopes and insights. J. Infect. Dis. 2014;210:668–670. doi: 10.1093/infdis/jiu210.
    1. Hofer U. Microbiome: Anelloviridae go viral. Nat. Rev. Microbiol. 2013;12:4–5.
    1. Schiemann M, et al. Torque teno virus load - inverse association with antibody-mediated rejection after kidney transplantation. Transplantation. 2017;101:360–367. doi: 10.1097/TP.0000000000001455.
    1. Simonetta F, et al. Torque teno virus load and acute rejection after orthotopic liver transplantation. Transplantation. 2017;101:219–221. doi: 10.1097/TP.0000000000001723.
    1. Takahashi K, Iwasa Y, Hijikata M, Mishiro S. Identification of a new human DNA virus (TTV-like mini virus, TLMV) intermediately related to TT virus and chicken anemia virus. Arch. Virol. 2000;145:979–993. doi: 10.1007/s007050050689.
    1. Ninomiya M, et al. Identification and genomic characterization of a novel human torque teno virus of 3.2 kb. J. Gen. Virol. 2007;88:1939–1944. doi: 10.1099/vir.0.82895-0.

Source: PubMed

3
Předplatit