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  • In the current study we monitored different groups at risk

    2020-10-16

    In the current study, we monitored different groups at risk for CMV reactivation. Similar to the findings from other groups, we observed CMV-reactivations with high-level viremia mostly during the first three months after alloHSCT only in the (D−/R+) and (D+/R+) group [[23], [24]]. Increasing IFN‐γ levels were detected from month three on in both groups, but more pronounced in the (D+/R+) group, indicating a beginning reconstitution of T-cell immunity. Enhanced IFN-γ levels in the (D+/R+) group are related to donor-derived, CMV-experienced T-cells, thereby facilitating boosted immune reconstitution. The overall less pronounced CMV-specific immune response in the high-risk group (D−/R+) is probably related to the transplantation of a CMV-naïve IT-901 and thus a delayed or absent virus-specific CD8+ T-cell recovery [[25], [26]]. Therefore, CMV replication has to be considered as a primary infection in these patients. Taken together, there is clear evidence that recovery of an adequate CMV-specific T-cell response is essential for controlling CMV viremia and disease. We were able to calculate a QF-threshold of 8.9 IU/ml (specificity = 100%; sensitivity = 42%), which correlates with protection from high-level viremia. However, the restricted number of patients and including of multiple episodes of QF-values and CMV-DNA levels in calculation of the threshold may limit the analysis. The IFN-γ threshold presented here was calculated with simultaneously acquired IFN-γ and CMV-DNA values. A similar threshold (7.6 IU/ml) was achieved when performing a prospective analysis using CMV-DNA levels with preceding IFN‐γ values to calculate the threshold. Similar to a study describing the performance of the QF-assay in lung transplant recipients, the ROC analysis showed a good practicability of the assay in predicting the risk for high-level viremia [27]. Notably, individual risk factors such as intensive immunosuppressive treatment of severe GVHD (grade III or IV), B-cell depletion with Rituximab or infection-related (bacterial meningitis) were associated with more frequent CMV complications and should be considered when assessing preemptive antiviral treatment [[23], [28]]. The threshold calculated in this study may be helpful to assess the risk for CMV-associated complications, but clearly needs to be interpreted cautiously in patients with additional risk factors. Interestingly, there was no CMV replication in the low risk group (D+/R−) and a decline of the CMV-specific T-cell response during 12 months after HSCT. Most likely, only CMV immunity and no virus has been transferred via HSCT to these patients.
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    Acknowledgements
    Introduction Age-accumulated decline in systemic immunity has been widely documented as a mechanism of the increasing morbidity and mortality that occur in the elderly [(Hadrup et al., 2006; Tu and Rao, 2016)]. The molecular mechanism of CD8+ T cell aging, characterized by an ongoing phenotype “shift”, can be reasonably identified as being largely due to repeated exposure to identical antigens in the elderly. In this scenario, ubiquitously latent cytomegalovirus (CMV) (the largest DNA herpesvirus) is widely acknowledged as the most robust antigenic contributor to the CD8+ T cell response due to episodic “subclinical” viral reactivation, at undetectable low levels, during its lifelong latency (Pawelec et al., 2012; Savva et al., 2013; Vescovini et al., 2007). Notably, almost all people of very advanced age are CMV carriers. Of interest, CD8+ T cells display some unexpected and unique subset-proportional shifts in people of very advanced age, compared to those in the general elderly (Arens et al., 2015; Riddell et al., 2015; Turner et al., 2014; Weekes et al., 1999; Wertheimer et al., 2014) (Farber et al., 2014). Therefore, how age-accumulated CMV repetitive responses enhance CD8+ T cell aging warrant exploration. Moreover, the reactivation of latent CMV infection is generally “silent” in immunocompetent individuals, whereas it causes severe disorders and even death in immunocompromised individuals. This markedly dimorphic outcome also raises the question of how CMV persistence episodically enhances the CD8+ T cell aging process (Turner et al., 2014).