Is Cytomegalovirus Prophylaxis Dispensable in Patients Receiving an mTOR Inhibitor–Based Immunosuppression? A Systematic Review and Meta-Analysis

Andrassy, Joachim; Hoffmann, Verena; Rentsch, Markus; Stangl, Manfred; Habicht, Antje; Meiser, Bruno; Fischereder, Michael; Jauch, Karl‐Walter; Guba, Markus

doi:10.1097/tp.0b013e3182708e56

Cited by 87 publications

(98 citation statements)

References 63 publications

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“…In contrast, the use of mammalian target of rapamycin (mTOR) inhibitors was more common among pediatric patients. A large amount of evidence supports the antiviral role of mTOR inhibitors, particularly in terms of a decreased risk for CMV infection (30,31), although this protective effect might have been diluted by the concomitant use of tacrolimus and the higher prevalence of CMVseronegative recipients (i.e. at risk of posttransplant primary infection) in the pediatric cohort.…”

Section: Discussionmentioning

confidence: 99%

Infectious Complications Following Small Bowel Transplantation

Silva

Juan

Fernández-Caamaño

et al. 2016

American Journal of Transplantation

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Microbiological spectrum and outcome of infectious complications following small bowel transplantation (SBT) have not been thoroughly characterized. We performed a retrospective analysis of all patients undergoing SBT from 2004 to 2013 in Spain. Sixty-nine patients underwent a total of 87 SBT procedures (65 pediatric, 22 adult). The median follow-up was 867 days. Overall, 81 transplant patients (93.1%) developed 263 episodes of infection (incidence rate: 2.81 episodes per 1000 transplant-days), with no significant differences between adult and pediatric populations. Most infections were bacterial (47.5%). Despite universal prophylaxis, 22 transplant patients (25.3%) developed cytomegalovirus disease, mainly in the form of enteritis. Specifically, 54 episodes of opportunistic infection (OI) occurred in 35 transplant patients. Infection was the major cause of mortality (17 of

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Section: Discussionmentioning

confidence: 99%

Infectious Complications Following Small Bowel Transplantation

Silva

Juan

Fernández-Caamaño

et al. 2016

American Journal of Transplantation

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“…The therapeutic immune suppression in transplant recipients with mTORC1 inhibitors has significantly reduced the incidence of HCMV reactivation (44,45), implying an antiviral role of targeting mTORC1 in clinical settings. Moorman et al discovered that the HCMV protein pUL38 interacts with TSC2 and activates mTORC1 by antagonizing TSC function (14).…”

Section: Discussionmentioning

confidence: 99%

Tuberous Sclerosis Complex Protein 2-Independent Activation of mTORC1 by Human Cytomegalovirus pUL38

Bai

Xuan

Liu

et al. 2015

J Virol

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The mammalian target of rapamycin complex 1 (mTORC1) controls cell growth and anabolic metabolism and is a critical host factor activated by human cytomegalovirus (HCMV) for successful infection. The multifunctional HCMV protein pUL38 previously has been reported to activate mTORC1 by binding to and antagonizing tuberous sclerosis complex protein 2 (TSC2) . pUL38 also plays a role in blocking endoplasmic reticulum stress-induced cell death during HCMV infection. In this study, we showed that a mutant pUL38 lacking the N-terminal 24 amino acids (pHA-UL38 25-331 ) was fully functional in suppressing cell death during infection. Interestingly, pHA-UL38 25-331 lost the ability to interact with TSC2 but retained the ability to activate mTORC1, although to a lesser extent than full-length pHA-UL38. Recombinant virus expressing pHA-UL38 25-331 replicated with ϳ10-fold less efficiency than the wild-type virus at a low multiplicity of infection (MOI), but it grew similarly well at a high MOI, suggesting an MOIdependent importance of pUL38-TSC2 interaction in supporting virus propagation. Site-directed mutational analysis identified a TQ motif at amino acid residues 23 and 24 as critical for pUL38 interaction with TSC2. Importantly, when expressed in isolation, the TQ/AA substitution mutant pHA-UL38 TQ/AA was capable of activating mTORC1 just like pHA-UL38 25-331 . We also created TSC2-null U373-MG cell lines by CRISPR genome editing and showed that pUL38 was capable of further increasing mTORC1 activity in TSC2-null cells. Therefore, this study identified the residues important for pUL38-TSC2 interaction and demonstrated that pUL38 can activate mTORC1 in both TSC2-dependent and -independent manners. IMPORTANCE HCMV, like other viruses, depends exclusively on its host cell to propagate. Therefore, it has developed methods to protect against host stress responses and to usurp cellular processes to complete its life cycle. mTORC1 is believed to be important for virus replication, and HCMV maintains high mTORC1 activity despite the stressful cellular environment associated with infection. mTORC1 inhibitors suppressed HCMV replication in vitro and reduced the incidence of HCMV reactivation in transplant recipients. We demonstrated that mTORC1 was activated by HCMV protein pUL38 in both TSC2-dependent and TSC2-independent manners. The pUL38-independent mode of mTORC1 activation also has been reported. These novel findings suggest the evolution of sophisticated approaches whereby HCMV activates mTORC1, indicating its importance in the biology and pathogenesis of HCMV.( Human cytomegalovirus (HCMV) is a member of the betaherpesvirus family with broad cell tropism. It is capable of escaping the immune surveillance and persists as a lifelong latent and recurrent infection in the host (1, 2). HCMV infection in adults and healthy people normally is asymptomatic or causes mild illness, but it can cause severe and life-threatening diseases in immunocompromised individuals, and importantly, HCMV congenital infection is a leadin...

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“…Several studies and meta-analysis have shown that the use of mammalian target of rapamycin inhibitors (mTORI, sirolimus, and everolimus), either de novo (13)(14)(15) or as a conversion strategy (16), are associated with lower rates of CMV infection. In all these trials, the population and management of CMV infection were largely heterogeneous with low representation of patients receiving no prophylaxis, who would benefit the most, primarily in transplant centers where CMV prophylaxis is not available or reimbursed.…”

Section: Introductionmentioning

confidence: 99%

Reduced Incidence of Cytomegalovirus Infection in Kidney Transplant Recipients Receiving Everolimus and Reduced Tacrolimus Doses

Tedesco‐Silva

Felipe

Ferreira

et al. 2015

American Journal of Transplantation

134

136

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Is Cytomegalovirus Prophylaxis Dispensable in Patients Receiving an mTOR Inhibitor–Based Immunosuppression? A Systematic Review and Meta-Analysis

Abstract: mTOR-inhibitor treatment either alone or in combination with CNIs reduces significantly the CMV incidence after organ transplantation. With the use of an mTOR-inhibitor, CMV prophylaxis may be dispensible.

Cited by 87 publications

References 63 publications

Infectious Complications Following Small Bowel Transplantation

Infectious Complications Following Small Bowel Transplantation

Tuberous Sclerosis Complex Protein 2-Independent Activation of mTORC1 by Human Cytomegalovirus pUL38

Reduced Incidence of Cytomegalovirus Infection in Kidney Transplant Recipients Receiving Everolimus and Reduced Tacrolimus Doses

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