Antibody-mediated rejection (AMR) is increasingly recognized as a significant complication of kidney transplantation. However, diagnosis for AMR remains a challenge due to lack of quantitative Food and Drug Administration-approved assays and the difficulty in discovering biomarkers that correlate with AMR. In this issue, Schiemann et al found that kidney transplant recipients who progressed to AMR had lower Torque Teno virus (TTV) load than recipients who did not develop AMR.1 This finding is particularly intriguing because it suggests that TTV levels could be monitored to predict whether recipients will develop AMR, but also raises intriguing questions about the role of TTV and related viruses in transplant diseases.
TTV are small nonenveloped viruses that encode a circular single-stranded DNA genome of approximately 3.8 kb. After its initial discovery in 1997, it was quickly recognized that TTV species have tremendous genetic diversity.2 In addition to TTV which are classified in the Alphatorquevirus genus within the Anelloviridae family, members of the Betatorquevirus and Gammatorquevirus genera also infect humans. TTV is commonly detected in the plasma of up to 90% of healthy individuals, with viral load ranging from 102 to 106 copies/mL.3,4 However, human anelloviruses including TTV are not direct causatives of disease and thus, considered nonpathogenic viruses.
Anellovirus burden is correlated with the degree of immunosuppression and organ transplant outcome. Exposure to increased doses of immunosuppressive drugs, corresponding to a state of lower functional immunity, is associated with increased TTV levels.5,6 Conversely, transplant recipients with lower levels of TTV were at greater risk of rejection, presumably mirroring a more active state of host immune function.5 Further, in patients who underwent autologous hematopoietic stem cell transplantation, high-dose chemotherapy caused a spike in plasma TTV levels that subsided to pretreatment baseline levels at a steady rate.7 This suggests that TTV could be a marker of immune reconstitution. However, the relationship between TTV and immunomodulation is not unique to transplantation. In fact, AIDS and congenital immunodeficiency are associated with increased viral load of TTV and related anelloviruses.8,9 Anelloviruses are also more frequently detected in plasma of febrile pediatric patients.10 Thus, taken together, anellovirus levels appear to be markers of functional immunocompetence.
How can these findings be translated to clinical use? One of the major challenges is that the “baseline” TTV viral load is highly variable between individuals. Studies have noted discrepancy in results between different TTV assays. However, coinfection by multiple TTV strains and other anelloviruses is also common. Genotyping studies have frequently found 3 to 6 different anellovirus genotypes in the plasma of healthy individuals. Given the extreme genetic diversity within the Anelloviridae family, it is plausible that part of this variability could be attributed to limited assay specificity that is unable to accurately capture the viral load of multiple variants of TTV and anelloviruses. It would be of interest to compare these TTV findings with the viral load of other human anelloviruses—Torque Teno Mini viruses (Betatorquevirus) and Torque Teno Midi Viruses (Gammatorquevirus)—that are also commonly detected in human plasma.
It is conceivable that once the details have been ironed out, TTV and anellovirus levels could be used to predict AMR and used to adjust immunosuppression to determine a safe level of immunosuppression. Thus, these levels could be a “viromarker” of too little, too much, or just right immunosuppression. The article by Sheimann provides the first snapshot of the utility of TTV levels as a viromarker.
1. Schiemann M, Puchhammer-Stöckl E, Eskandary F, et al. Torque teno virus load—inverse association with antibody-mediated rejection after kidney transplantation. Transplantation
2. Biagini P. Classification of TTV and related viruses (anelloviruses). Curr Top Microbiol Immunol
3. Pollicino T, Raffa G, Squadrito G, et al. TT virus has a ubiquitous diffusion in human body tissues: analyses of paired serum and tissue samples. J Viral Hepat
4. Haloschan M, Bettesch R, Gorzer I, et al. TTV DNA plasma load and its association with age, gender, and HCMV IgG serostatus in healthy adults. Age (Dordr)
5. De Vlaminck I, Khush KK, Strehl C, et al. Temporal response of the human virome to immunosuppression and antiviral therapy. Cell
6. Gorzer I, Haloschan M, Jaksch P, et al. Plasma DNA levels of Torque teno virus and immunosuppression after lung transplantation. J Heart Lung Transplant
7. Focosi D, Maggi F, Albani M, et al. Torquetenovirus viremia kinetics after autologous stem cell transplantation are predictable and may serve as a surrogate marker of functional immune reconstitution. J Clin Virol
8. Li L, Deng X, Linsuwanon P, et al. AIDS alters the commensal plasma virome. J Virol
9. Maggi F, Pifferi M, Michelucci A, et al. Torque teno virus viremia load size in patients with selected congenital defects of innate immunity. Clin Vaccine Immunol
10. McElvania TeKippe E, Wylie KM, Deych E, et al. Increased prevalence of anellovirus in pediatric patients with fever. PLoS One