Torque Teno virus load as a surrogate marker for the net state of immunosuppression: The beneficial side of the virome

Abstract

Transplant physicians still face challenges in assessing the net state of immunosuppression of their patients, which results from the complex interaction among pretransplant conditions, induction and maintenance immunosuppressive regimens, graft function, antirejection therapies, nutritional state and underlying comorbidities, and other factors. Therapeutic drug monitoring (TDM) of immunosuppressive agents appears as the most widely used strategy in current clinical practice. However, this approach is strictly pharmacokinetic in nature and does not capture the interindividual variability in T cell responses at a given concentration of calcineurin or mTOR inhibitors, or the synergistic effect of combination immunosuppressive regimens. Therefore, the correlation of TDM with clinical events seems to be relatively poor, particularly for posttransplant infection. For instance, the presence of high tacrolimus trough levels (>7.15 ng/mL) at the first month was found to have a sensitivity and specificity of only 55.6% and 63.4%, respectively, to predict infection in a large cohort of more than 2000 kidney transplant (KT) recipients.1Yin S Song T Jiang Y Li X Fan Y Lin T. Tacrolimus trough level at the first month may predict renal transplantation outcomes among living Chinese kidney transplant patients: a propensity score-matched analysis.Ther Drug Monit. 2019; 41: 308-316Crossref PubMed Scopus (8) Google Scholar On the other hand, the implementation of functional biomarkers, such as intracellular ATP production by phytohemagglutinin-stimulated lymphocytes, has been impeded by logistical and economic barriers and suboptimal predictive accuracy (particularly for posttransplant infectious events).2Fernandez-Ruiz M Kumar D Humar A. Clinical immune-monitoring strategies for predicting infection risk in solid organ transplantation.Clin Transl Immunology. 2014; 3: e12Crossref PubMed Google Scholar Our understanding of the paradigm of host–pathogen interactions has been questioned by the ongoing discovery of the human virome—a vast diversity of RNA and DNA viral communities that maintain a dynamic, bidirectional relationship with host immunity at multiple anatomic sites. The virome embodies a complex ecosystem that encompasses eukaryotic viruses causing persistent latent infection (eg, papillomaviruses or herpesviruses), viruses integrated into the human genome (endogenous retroviruses), and prokaryotic viruses (bacteriophages). Increasing research efforts are being devoted to the characterization of gut and skin viromes due to potential therapeutic implications. In this line, it has been suggested that certain host-specific virotypes might be involved in the pathogenesis of inflammatory bowel disease.3Santiago-Rodríguez TM Hollister EB. Human virome and disease: high-throughput sequencing for virus discovery, identification of phage-bacteria dysbiosis and development of therapeutic approaches with emphasis on the human gut.Viruses. 2019; 11 (pii): E656Crossref PubMed Scopus (73) Google Scholar Next-generation sequencing technologies are also shaping our knowledge of the blood virome and leading to the identification of emerging pathogens, which is of particular relevance for the safety of blood transfusion practices.4Moustafa A Xie C Kirkness E et al.The blood DNA virome in 8,000 humans.PLoS Pathog. 2017; 13: e1006292Crossref PubMed Scopus (170) Google Scholar Anelloviruses are nonenveloped, circular, single-stranded DNA viruses that account for the largest fraction of the blood genome in healthy individuals. Torque Teno virus (TTV)—from the Latin words torques (neck-lace) and tenuis (thin)—is the prototypical, and first discovered (1997), member of the Anelloviridae family. Like other virome components, TTV holds the status of “orphan virus” since no causal association has been demonstrated to date with attributable clinical manifestations.5Focosi D Antonelli G Pistello M Maggi F. Torquetenovirus: the human virome from bench to bedside.Clin Microbiol Infect. 2016; 22: 589-593Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar The replication of this commensal viral community is under close control by the adaptive arm of the immune system, with an estimated 90% of the virions in plasma being cleared and replenished and as many as 3.8 × 1010 virions being generated per day.6Maggi F Pistello M Vatteroni M 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: 11999-12004Crossref PubMed Scopus (65) Google Scholar Posttransplant immunosuppression impairs such a fine balance. Thus, the inverse correlation existing between immune competence and anellovirus replication offers a mechanistic rationale for monitoring TTV DNAemia as a functional surrogate for the net state of immunosuppression after KT.5Focosi D Antonelli G Pistello M Maggi F. Torquetenovirus: the human virome from bench to bedside.Clin Microbiol Infect. 2016; 22: 589-593Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar In the present issue of the American Journal of Transplantation, Doberer et al report the results from a prospective trial (TTV-POET) that recruited 386 consecutive KT recipients at the Medical University Vienna in which plasma TTV viral loads were monitored at scheduled times during the first 12 months, resulting in more than 3200 individual measurements.7Doberer K, Schiemann M, Strassl R, et al. Torque Teno virus for risk stratification of graft rejection and infection in kidney transplant recipients - a prospective observational trial [published online ahead of print 2020]. Am J Transplant. https://doi.org/10.1111/ajt.15810Google Scholar The characteristics of the study cohort were representative of the KT population in most European centers, including the proportion of donor/recipient cytomegalovirus (CMV) serology mismatch (14%) and the prophylaxis regimens used. The inclusion of 9% of sensitized patients with preformed donor-specific antibodies would explain the relatively high 1-year cumulative rate found for acute graft rejection (18%). In agreement with the tested hypothesis, recipients experiencing rejection had lower TTV levels than those without rejection, although it should be noted that this analysis was restricted to only 37 patients who underwent for-cause graft biopsy and beyond the third posttransplant month (ie, once the TTV load had stabilized). The authors reported that each log increase in TTV load decreased the risk of rejection by 22% (odds ratio [OR]: 0.78; 95% confidence interval [CI]: 0.62-0.97). On the other hand, all 274 patients with available follow-up after month 3 were included in the analysis of the predictive capacity of TTV levels for posttransplant infection. As expected, most episodes were bacterial in nature and involved the urinary and the respiratory tracts, although opportunistic pathogens (such as CMV or Pneumocystis jirovecii) were documented in about one third of the cases. TTV loads were significantly higher among recipients suffering from posttransplant infection, and the odds increased by 11% with every log increase (OR: 1.11; 95% CI: 1.06-1.15). Interestingly, the largest effect size was obtained for BK infection, CMV disease, and infections restricted to opportunistic pathogens, supporting the notion that TTV replication control is mainly exerted by the T cell–mediated immunity. Moreover, both associations were consistent across a set of sensitivity analyses.7Doberer K, Schiemann M, Strassl R, et al. Torque Teno virus for risk stratification of graft rejection and infection in kidney transplant recipients - a prospective observational trial [published online ahead of print 2020]. Am J Transplant. https://doi.org/10.1111/ajt.15810Google Scholar In addition to its single-center design (a critical point considering the lack of international standards for TTV PCR assays), some limitations must be noted. Although TTV was longitudinally measured at multiple time points, the authors did not explore viral kinetics (eg, ascending or decreasing slopes or doubling times between consecutive monitoring points) but rather used this biomarker at 3-month intervals as a static snapshot. The predictive accuracy of viral loads assessed earlier was not analyzed, despite the fact that the majority of episodes of infection take place in the preceding period. The authors should be applauded for their well-performed research, whose results essentially align with those reported by our group and others.8Fernández-Ruiz M Albert E Giménez E et al.Monitoring of alphatorquevirus DNA levels for the prediction of immunosuppression-related complications after kidney transplantation.Am J Transplant. 2019; 19: 1139-1149Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar,9Rezahosseini O Drabe CH Sørensen SS et al.Torque-Teno virus viral load as a potential endogenous marker of immune function in solid organ transplantation.Transplant Rev (Orlando). 2019; 33: 137-144Crossref PubMed Scopus (48) Google Scholar In addition, the study by Doberer et al provide 2 relevant contributions to the emerging field of TTV monitoring in the KT setting. First, predictive TTV viral loads were assessed at a median of 14 and 27 days before rejection and infectious episodes were diagnosed, respectively, thus reinforcing its potential use as an early risk marker. Second, and on the basis of the high negative predictive values observed for certain thresholds, the authors propose an optimal range for TTV viral load (from 1 × 106 to 1 × 108 copies/mL) to minimize the risk for rejection and infection after KT. However, it seems that this performance would be lower for identifying patients at an increased risk of actually developing infection or rejection if viral loads are above or below the range limits, respectively, because positive predictive values do not exceed 50%. It is hoped that these proposed cutoff values will be externally validated in separate cohorts, although advances are to be made in the standardization of PCR assays and reporting units and the definition of optimal blood compartments and timepoints for viral load quantification. It will be also interesting to investigate the correlation between TTV levels and novel assays aimed at quantifying both innate and adaptive immune compartments, as well as the potential improvement in predictive capacity that would result from combining these biomarkers.10Mian M Natori Y Ferreira V et al.Evaluation of a novel global immunity assay to predict infection in organ transplant recipients.Clin Infect Dis. 2018; 66: 1392-1397Crossref PubMed Scopus (32) Google Scholar In the meanwhile, the study by Doberer et al is to be welcomed as a major step in the application of human virome as a convenient surrogate for the net state of immunosuppression in the KT population. The author of this manuscript has no conflicts of interest to disclose as described by the American Journal of Transplantation. The author holds a research contract “Miguel Servet” (CP 18/00073) from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III.

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