The non‐pathogenic and ubiquitous Torque Teno virus (TTV) is associated with immunosuppression in solid organ transplant recipients. Studies in kidney transplant patients proposed TTV quantification for risk stratification of graft rejection and infection. In this prospective trial (DRKS00012335) 386 consecutive kidney transplant recipients were subjected to longitudinal per‐protocol monitoring of plasma TTV load by PCR for 12 months post‐transplantation. TTV load peaked at the end of month 3 post‐transplantation and reached steady state thereafter. TTV load after the end of month 3 was analyzed in the context of subsequent rejection diagnosed by indication biopsy and infection within the first year post‐transplantation, respectively. Each log increase in TTV load decreased the odds for rejection by 22% (OR 0.78, 95%CI 0.62‐0.97; P=.027) and increased the odds for infection by 11% (OR 1.11, 95%CI 1.06‐1.15; P<.001). TTV was quantified at a median of 14 days before rejection was diagnosed and 27 days before onset of infection, respectively. We defined a TTV load between 1x10⁶ and 1x10⁸ copies/mL as optimal range to minimize the risk for rejection and infection. These data support the initiation of an interventional trial assessing the efficacy of TTV‐guided immunosuppression to reduce infection and graft rejection in kidney transplant recipients.

The human Torque Teno virus (TTV) causes persistent viremia in most immunocompetent individuals. Elevated TTV levels are observed after solid organ transplantation and are related to the extent of immunosuppression especially during the phase of maintenance immunosuppression. However, the extent to which the TTV increase in the early phase post-transplantation is associated with the patient’s immunosuppressive state is unclear. In this study, we assessed the TTV increase dynamics in detail during the first three months after lung transplantation under a defined immunosuppressive regimen and in relation to the pre-transplant TTV level. Forty-six lung transplant recipients (LTRs) were included in this prospective longitudinal study. All received alemtuzumab induction combined with tacrolimus and corticosteroids immunosuppressive therapy. Plasma TTV DNA was monitored before transplantation and regularly within the first three months post-transplantation (n = 320 samples; mean sampling interval: 12.2 days). In 43/46 LTRs (93%), TTV DNA was detectable before transplantation (median 4.4 log₁₀ copies/mL; range: 2.0–6.4). All 46 LTRs showed a TTV increase post-transplantation, which followed a sigmoidal-shaped curve before the median peak level of 9.4 log₁₀ copies/mL (range: 7.6–10.7) was reached at a median of day 67 (range: 41–92). The individual TTV DNA doubling times (range: 1.4–20.1 days) significantly correlated with the pre-transplant TTV levels calculated over 30 or 60 days post-transplantation (r = 0.61, 0.54, respectively; both P < 0.001), but did not correlate with the mean tacrolimus blood levels. Pre-transplant TTV levels were not associated with time and level of the patients’ post-transplant TTV peak load. The TTV level may be used to mirror the state of immunosuppression only after the patients’ initial peak TTV level is reached.

Background Antibody-mediated rejection (AMR) represents one of the cardinal causes of late allograft loss after kidney transplantation, and there is great need for noninvasive tools improving early diagnosis of this rejection type. One promising strategy might be the quantification of peripheral blood DNA levels of the highly prevalent and apathogenic Torque Teno virus (TTV), which might mirror the overall level of immunosuppression and thus help determine the risk of alloimmune response. Methods To assess the association between TTV load in the peripheral blood and AMR, 715 kidney transplant recipients (median, 6.3 years posttransplantation) were subjected to a systematical cross-sectional AMR screening and, in parallel, TTV quantification. Results Eighty-six of these recipients had donor-specific antibodies and underwent protocol biopsy, AMR-positive patients (n = 46) showed only 25% of the TTV levels measured in patients without AMR (P = 0.003). In a generalized linear model, higher TTV levels were associated with a decreased risk for AMR after adjustment for potential confounders (risk ratio 0.94 per TTV log level; 95% confidence interval 0.90-0.99; P = 0.02). Conclusions Future studies will have to clarify whether longitudinal assessment of TTV load might predict AMR risk and help guide the type and intensity of immunosuppression to prevent antibody-mediated graft injury.

In lung transplant patients undergoing immunosuppression, more than one human cytomegalovirus (HCMV) genotype may emerge during follow-up, and this could be critical for the outcome of HCMV infection. Up to now, many cases of infection with multiple HCMV genotypes were probably overlooked due to the limitations of the current genotyping approaches. We have now analyzed mixed-genotype infections in 17 clinical samples from 9 lung transplant patients using the highly sensitive ultradeep-pyrosequencing (UDPS) technology. UDPS genotyping was performed at three variable HCMV genes, coding for glycoprotein N (gN), glycoprotein O (gO), and UL139. Simultaneous analysis of a mean of 10,430 sequence reads per amplicon allowed the relative amounts of distinct genotypes in the samples to be determined down to 0.1% to 1% abundance. Complex mixtures of up to six different HCMV genotypes per sample were observed. In all samples, no more than two major genotypes accounted for at least 88% of the HCMV DNA load, and these were often accompanied by up to four low-abundance genotypes at frequencies of 0.1% to 8.6%. No evidence for the emergence of new genotypes or sequence changes over time was observed. However, analysis of different samples withdrawn from the same patients at different time points revealed that the relative levels of replication of the individual HCMV genotypes changed within a mixed-genotype population upon reemergence of the virus. Our data show for the first time that, similar to what has been hypothesized for the murine model, HCMV reactivation in humans seems to occur stochastically.