Torque Teno Virus as a Potential Biomarker for Complications and Survival After Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Impaired immune reconstitution after allogeneic hematopoietic stem cell transplantation (HSCT) contributes to increased risk of cancer relapse and infection resulting in significant morbidity and mortality. Unfortunately, effective strategies to functionally assess the quality of immune reconstitution are still missing. Quantification of in vivo replication of the ubiquitous, non-pathogenic virus Torque Teno Virus (TTV) has been reported in small series as a test to functionally evaluate the quality of post-transplant immune reconstitution. In the present study, we analyzed by quantitative PCR TTV titers in plasma samples from a large cohort of 168 allogeneic HSCT recipients. Our analysis confirms that TTV titers peaked at 100 days post-transplant, followed by progressive normalization thereafter. Negative correlation of TTV titers with T cell absolute numbers during the first year post-transplant points to the restoration of an active anti-TTV immunity. Univariable and multivariable linear regression analysis demonstrated that donor CMV positive serostatus, donor type and immune suppression resulting from GVHD treatment affected the restoration of anti-TTV immunity. Importantly, higher TTV titers at 100 days after transplantation were associated with worse overall survival and higher risk of acute GVHD and infections. Our results provide new insights into the factors affecting the dynamics of TTV replication and indicate that TTV is a potentially useful biomarker to assess immune reconstitution and to predict complications and outcomes of allogeneic HSCT.

Unmasking viral sequences by metagenomic next-generation sequencing in adult human blood samples during steroid-refractory/dependent graft-versus-host disease

“…Among allo-HSCT recipients, two studies failed to demonstrate any association between TTV viremia and immune-related complication or other viral reactivations [ 28 , 33 ], while a third reported higher TTV viremia in patients receiving corticosteroids for GvHD [ 29 ]. A recent study found higher TTV VL at 100 days post-transplantation predicts worse overall survival, and a higher risk of acute GvHD and infections [ 34 ]. Finally, a mNGS study revealed increased detection rates and number of Anelloviridae sequences in stool samples of allo-HSCT recipients several weeks after developing digestive GvHD [ 5 ], suggesting a consequence of GvHD-associated inflammation and/or immunosuppressive therapy.…”

Torque Teno Virus Viral Load as a Marker of Immune Function in Allogeneic Haematopoietic Stem Cell Transplantation Recipients

“…This correlation can be explained by the absolute lymphocyte count reconstitution post engraftment, which then serves as a TTV replication reservoir, thus avoiding extrapolation between TTV and T-cell function. Indeed, as suggested by Pradier et al, the correlation between T-cell subtype count and TTV viral load can vary according to the interval post-transplant [ 5 ]. This result highlights the need for new markers to evaluate lymphocyte function.…”

“…The use of an immune functional assay (IFA) such as the assessment of post-stimulation T-cell proliferation capacity could fill this need but its implementation in clinical practice remains difficult. TTV could be interesting as a biomarker to estimate immune function and finally to predict infectious and/or clinical events related to the immune system [ 5 , 9 , 22 , 26 , 30 ].…”

“…During the immune reconstitution period, tools to effectively measure the individual degree of immunosuppression are needed. Absolute lymphocyte counts, such as counts of T-cell subtype populations, are currently used as biomarkers of immune reconstitution, although this is not informative of their function [ 5 , 6 , 7 ]. A simple blood biomarker mirroring T-cell function would be useful, and measuring the blood viral load of torque teno virus (TTV) may be of interest in this context.…”

Viral Infections in HSCT: Detection, Monitoring, Clinical Management, and Immunologic Implications

“…TTV viremia kinetic was then determined on a large series of HSCT recipients and analyzed in multivariable analysis: failure to clear TTV was linked to CMV, GVHD and unrelated donor, with patients bearing higher day 100 TTV levels showing a worse survival and a higher risk of severe aGVHD. The relationship between T-cell depletion and TTV is far from being disclosed, and available preliminary data open the question of whether a more accurate assessment of immunocompetence could be possible by TTV rather than by mere lymphocyte ( 155 ).…”