Cytomegalovirus reactivation: Another reason to minimize graft ischemia/reperfusion Article Swipe

The author comments on the importance of Zhang et al’s (page 2421) observation that ischemia and reperfusion can trigger CMV reactivation after solid organ transplantation. The author comments on the importance of Zhang et al’s (page 2421) observation that ischemia and reperfusion can trigger CMV reactivation after solid organ transplantation. Despite advances in viral monitoring, pharmacologic antiviral agents, and strategies that include prophylaxis and preemptive therapy, cytomegalovirus (CMV) reactivation remains a significant problem in solid organ transplantation.1Freeman Jr, RB The ‘indirect’ effects of cytomegalovirus infection.Am J Transplant. 2009; 9: 2453-2458Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar It has been suggested recently that CMV latency is influenced by three main forces: inflammation, CMV-specific immunity, and epigenetic regulation of the viral promoter.2Seckert CK Griessl M Buttner JK et al.Immune surveillance of cytomegalovirus latency and reactivation in murine models: link to memory inflation.in: Reddehase MJ Cytomegaloviruses. Caister Academic Press, Norfolk, UK2013: 374-416Google Scholar If true, then allogeneic transplantation may contribute to reactivation in multiple ways, including inflammation induced by allogeneic stimulation or ischemia/reperfusion, and the accompanying requisite immunosuppression. As it stands though, current clinical constructs require immunosuppression, thereby clouding insight into the individual contributions of immunosuppression and ischemia/reperfusion on viral activity. In the current issue, Zhang et al3Zhang Z, Qiu L, Yan S, et al. A clinically relevant murine model unmasks a ‘Two-Hit’ mechanism for reactivation and dissemination of cytomegalovirus following kidney transplantation. Am J Transplant. 2019. [Epub ahead of print]. https://doi.org/10.1111/ajt.15376.Google Scholar utilize their well-described renal transplant model to explore these contributions. For this work, mice received either allogeneic or syngeneic renal transplantation with or without a clinically relevant immunosuppression regimen of tacrolimus, antilymphocyte therapy, and steroids. The simple yet clever constructs with syngeneic transplantation allow the authors to evaluate the individual effects of ischemia/reperfusion on viral reactivation. Although it perhaps was not their primary objective, they also make important observations on the contribution of immunosuppression to viral reactivation. There is a longstanding interest in ischemia/reperfusion and its negative impact on graft function, which has become particularly keen in the era of deceased donor transplantation.4Bon D Chatauret N Giraud S Thuillier R Favreau F Hauet T New strategies to optimize kidney recovery and preservation in transplantation.Nat Rev Nephrol. 2012; 8: 339Crossref PubMed Scopus (92) Google Scholar CMV has also been associated with worsened graft outcomes, but the association with ischemia/reperfusion until now has been unproven. This question is practically impossible to study in humans, requiring transplantation of a CMV-infected kidney to a CMV-negative haploidentical twin, a clinical rarity for sure. In the past, our group attempted to study this relationship using in situ ischemia/reperfusion of latently infected murine hosts by clamping the renal pedicle for various periods. We were unsuccessful in showing viral reactivation (C.H. Cook, A.A. Bickerstaff, & J.-J. Wang, 2006, unpublished data); however, in this in situ model, hosts had preexisting CMV-specific immunity that could influence reactivation. Use of a syngeneic murine renal transplant model with a latently infected donor and naive recipient (D+R−) allows investigation of ischemia/reperfusion in isolation, and Zhang et al3Zhang Z, Qiu L, Yan S, et al. A clinically relevant murine model unmasks a ‘Two-Hit’ mechanism for reactivation and dissemination of cytomegalovirus following kidney transplantation. Am J Transplant. 2019. [Epub ahead of print]. https://doi.org/10.1111/ajt.15376.Google Scholar have clearly shown that ischemia/reperfusion alone can trigger CMV reactivation. Thus in addition to the known detrimental effects of ischemia/reperfusion on graft function, preventing CMV reactivation gives us another very important reason to minimize graft ischemia/reperfusion injury. Because CMV causes disease primarily in immunocompromised hosts, there has been a longstanding assumption that immunosuppression contributes significantly to CMV reactivation. If true then for transplant patients, immune suppression happens at just the wrong time—particularly for seronegative recipients of seropositive organs that lack any immunity to CMV. For clinical transplantation, this has been impossible to study given the ethical limitations of separating immunosuppression from allogeneic transplantation. Use of rodent models allows these influences to be dissociated, and Bruning et al5Bruning JH Bruggeman CA van Boven CP van Breda Vriesman PJ Passive transfer of cytomegalovirus by cardiac and renal organ transplants in a rat model.Transplantation. 1986; 41: 695-698Crossref PubMed Scopus (30) Google Scholar were among the first to use such models to show that immunosuppression enhances reactivation and CMV transmission to a naive host. In the current issue, Zhang et al3Zhang Z, Qiu L, Yan S, et al. A clinically relevant murine model unmasks a ‘Two-Hit’ mechanism for reactivation and dissemination of cytomegalovirus following kidney transplantation. Am J Transplant. 2019. [Epub ahead of print]. https://doi.org/10.1111/ajt.15376.Google Scholar use a more clinically relevant immunosuppression regimen to show that immunosuppressed mice have significantly higher viral loads after syngeneic transplantation, confirming the impact of immunosuppression in CMV reactivation after transplantation. They also confirmed the clinical suspicion that immunosuppression impairs the development of CMV-specific immunity after reactivation. This makes sense, given both the importance of T cells in controlling CMV and that most of the immunosuppression regimen is aimed at blocking novel T cell responses, thereby allowing CMV to replicate more freely without this important control. This finding gives further support to the concept of inducing CMV-specific immunity before donor-positive recipient-negative (D+R−) transplantation. Their model can serve as an important platform for testing the impact of CMV immunization in the D+R− setting, and how various immunosuppressive regimens impact preexisting CMV-specific immunity. Although not done in this series of investigations, this model also affords the opportunity to investigate exactly which component of an immunosuppressive regimen has the greatest impact on viral reactivation. For example, steroids have been inconsistently associated with reactivation in immunocompetent hosts,6Cook CH Martin LC Yenchar JK et al.Occult herpes family viral infections are endemic in critically ill surgical patients.Crit Care Med. 2003; 31: 1923-1929Crossref PubMed Scopus (97) Google Scholar, 7Ong DSY Bonten MJM Spitoni C et al.Epidemiology of multiple herpes viremia in previously immunocompetent patients with septic shock.Clin Infect Dis. 2017; 64: 1204-1210Crossref PubMed Scopus (74) Google Scholar, 8Frantzeskaki FG Karampi ES Kottaridi C et al.Cytomegalovirus reactivation in a general, nonimmunosuppressed intensive care unit population: incidence, risk factors, associations with organ dysfunction, and inflammatory biomarkers.J Crit Care. 2015; 30: 276-281Crossref PubMed Scopus (59) Google Scholar but may actually impair reactivation after allogeneic transplantation.9Forster MR Bickerstaff AA Wang J-J Zimmerman PD Cook CH Allogeneic stimulation causes transcriptional reactivation of latent murine cytomegalovirus.Transplant Proc. 2009; 41: 1927-1931Crossref PubMed Scopus (7) Google Scholar It would therefore be of interest to determine whether steroids alone enhance or impair viral reactivation in the syngeneic IR model. Although it is admittedly unlikely that steroids would be chosen or abandoned from a regimen solely based on their impact on CMV, evaluation of the impact of individual components or combinations of immunosuppressive agents on CMV reactivation might prove to be clinically very useful. The influences of epigenetic regulation on cytomegalovirus latency and reactivation have been recently described. It is now clear that epigenetic mechanisms influence both development of latency and reactivation of CMV (reviewed in ref. 10Liu XF Wang X Yan S Zhang Z Abecassis M Hummel M Epigenetic control of cytomegalovirus latency and reactivation.Viruses. 2013; 5: 1325-1345Crossref PubMed Scopus (34) Google Scholar). Given the enhancement of CMV reactivation by immunosuppression, it is possible that immunosuppressive regimens influence these epigenetic mechanisms. In the current issue, Zheng et al3Zhang Z, Qiu L, Yan S, et al. A clinically relevant murine model unmasks a ‘Two-Hit’ mechanism for reactivation and dissemination of cytomegalovirus following kidney transplantation. Am J Transplant. 2019. [Epub ahead of print]. https://doi.org/10.1111/ajt.15376.Google Scholar confirm the influence of allogeneic stimulation on several epigenetic components, and importantly show that immunosuppression has no influence on these mechanisms. Thus the enhancement of virus activity by immunosuppression appears to be consequent to impacts on immune function and not the virus itself. In conclusion, the work by Zhang et al in the current issue is the next in a series of important contributions from a group with almost two decades experience in this area. In solid organ transplantation, hosts receive allogeneic stimulation, ischemia, and reperfusion of their new graft, and concomitant immunosuppression all in the same package. This makes the recipient ripe for reactivation episodes, but clinically it has been heretofore impossible to tease out which of these variables is to blame for CMV reactivation. Use of their clinically relevant model has allowed continued dissection of the influences of CMV reactivation after transplantation with approaches not possible in human subjects. Most importantly, their work emphasizes the impact of ischemia-reperfusion on viral reactivation and gives us yet another strong reason to maintain our focus on optimizing pretransplant graft treatment to enhance long-term outcomes. The author of this manuscript has no conflicts of interest to disclose as described by the American Journal of Transplantation. ErratumAmerican Journal of TransplantationVol. 20Issue 3PreviewZhang Z, Qiu L, Yan S, et al. A clinically relevant murine model unmasks a “two-hit” mechanism for reactivation and dissemination of cytomegalovirus after kidney transplant. Am J Transplant 2019;19(9):2421-2433. https://doi.org/10.1111/ajt.15376 Full-Text PDF Open Archive