CMV Prevention and Treatment in Transplantation: What’s New in 2019

Stern, Anat; Papanicolaou, Genovefa A.

doi:10.1007/s11908-019-0699-0

Cited by 25 publications

(26 citation statements)

References 81 publications

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“…The development of active immunization for HCMV is a major public health priority, and a number of candidate vaccines have been evaluated in clinical trials as well as preclinical models. However, no effective vaccine for HCMV is currently available [50][51][52][53][54][55][56].…”

Section: Introductionmentioning

confidence: 99%

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

Adamson

Nevels

2020

Viruses

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The human cytomegalovirus (HCMV), one of eight human herpesviruses, establishes lifelong latent infections in most people worldwide. Primary or reactivated HCMV infections cause severe disease in immunosuppressed patients and congenital defects in children. There is no vaccine for HCMV, and the currently approved antivirals come with major limitations. Most approved HCMV antivirals target late molecular processes in the viral replication cycle including DNA replication and packaging. “Bright and early” events in HCMV infection have not been exploited for systemic prevention or treatment of disease. Initiation of HCMV replication depends on transcription from the viral major immediate-early (IE) gene. Alternative transcripts produced from this gene give rise to the IE1 and IE2 families of viral proteins, which localize to the host cell nucleus. The IE1 and IE2 proteins are believed to control all subsequent early and late events in HCMV replication, including reactivation from latency, in part by antagonizing intrinsic and innate immune responses. Here we provide an update on the regulation of major IE gene expression and the functions of IE1 and IE2 proteins. We will relate this insight to experimental approaches that target IE gene expression or protein function via molecular gene silencing and editing or small chemical inhibitors.

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Section: Introductionmentioning

confidence: 99%

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

Adamson

Nevels

2020

Viruses

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“…Given both subjects are (D-/R+), we assume pure reactivation in the case subject rather than primary infection. Additionally, the use of patient's that received no induction chemotherapy and no CMV prophylaxis reduces the potential complications that may be associated with lymphodepleting induction regimens and subsequent immune reconstitution and the potential impact that CMV chemoprophylaxis may have on cell-mediated immunity ( 42 , 76 ). As the case subject developed CMV viremia between the 3- and 6-month visits, samples for both the case and control were selected from the 3-month visit (i.e., prior to development of CMV reactivation in the case subject).…”

Section: Resultsmentioning

confidence: 99%

Transcriptional Profiling of CD8+ CMV-Specific T Cell Functional Subsets Obtained Using a Modified Method for Isolating High-Quality RNA From Fixed and Permeabilized Cells

2020

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Previous studies suggest that the presence of antigen-specific polyfunctional T cells is correlated with improved pathogen clearance, disease control, and clinical outcomes; however, the molecular mechanisms responsible for the generation, function, and survival of polyfunctional T cells remain unknown. The study of polyfunctional T cells has been, in part, limited by the need for intracellular cytokine staining (ICS), necessitating fixation and cell membrane permeabilization that leads to unacceptable degradation of RNA. Adopting elements from prior research efforts, we developed and optimized a modified protocol for the isolation of high-quality RNA (i.e., RIN > 7) from primary human T cells following aldehyde-fixation, detergent-based permeabilization, intracellular cytokines staining, and sorting. Additionally, this method also demonstrated utility preserving RNA when staining for transcription factors. This modified protocol utilizes an optimized combination of an RNase inhibitor and high-salt buffer that is cost-effective while maintaining the ability to identify and resolve cell populations for sorting. Overall, this protocol resulted in minimal loss of RNA integrity, quality, and quantity during cytoplasmic staining of cytokines and subsequent flourescence-activated cell sorting. Using this technique, we obtained the transcriptional profiles of functional subsets (i.e., non-functional, monofunctional, bifunctional, polyfunctional) of CMV-specific CD8+T cells. Our analyses demonstrated that these functional subsets are molecularly distinct, and that polyfunctional T cells are uniquely enriched for transcripts involved in viral response, inflammation, cell survival, proliferation, and metabolism when compared to monofunctional cells. Polyfunctional T cells demonstrate reduced activation-induced cell death and increased proliferation after antigen re-challenge. Further in silico analysis of transcriptional data suggested a critical role for STAT5 transcriptional activity in polyfunctional cell activation. Pharmacologic inhibition of STAT5 was associated with a significant reduction in polyfunctional cell cytokine expression and proliferation, demonstrating the requirement of STAT5 activity not only for proliferation and cell survival, but also cytokine expression. Finally, we confirmed this association between CMV-specific CD8+ polyfunctionality with STAT5 signaling also exists in immunosuppressed transplant recipients using single cell transcriptomics, indicating that results from this study may translate to this vulnerable patient population. Collectively, these results shed light on the mechanisms governing polyfunctional T cell function and survival and may ultimately inform multiple areas of immunology, including but not limited to the development of new vaccines, CAR-T cell therapies, and adoptive T cell transfer.

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“…It was approved for oral or intravenous use by the Food and Drug Administration for CMV prophylaxis in allogeneic stem cell transplant recipients in 2017 [46]. However, the clinical experience in letermovir for treatment is limited [47]. Maribavir and brincidofovir are currently in clinical trials for CMV treatment.…”

Section: Discussionmentioning

confidence: 99%

Early diagnosis and successful treatment of cytomegalovirus peritonitis in children with primary nephrotic syndrome: case series and literature review

et al. 2020

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Cytomegalovirus (CMV) is a major pathogen in immunocompromised population and CMV infections in immunocompromised patients cause substantial morbidity and mortality. The common clinical manifestations of CMV infection are pneumonia, hepatitis, colitis and so on, while CMV peritonitis without gut perforation is rare. Reviewing the literature, CMV peritonitis in patients with nephrotic syndrome (NS) had not been reported. Only four cases of CMV peritonitis without gut perforation were reported in adults with other diseases. Two cases were diagnosed by reversetranscription polymerase chain reaction (RT-PCR) of ascites while the other two cases by histopathological examination of peritoneal tissue. We report four cases of primary nephrotic syndrome complicated with CMV peritonitis. Four cases all diagnosed by RT-PCR of ascites (659-455 000 copies/mL). We mainly discusses the diagnosis and treatment of CMV peritonitis without gut perforation.

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CMV Prevention and Treatment in Transplantation: What’s New in 2019

Cited by 25 publications

References 81 publications

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

Transcriptional Profiling of CD8+ CMV-Specific T Cell Functional Subsets Obtained Using a Modified Method for Isolating High-Quality RNA From Fixed and Permeabilized Cells

Early diagnosis and successful treatment of cytomegalovirus peritonitis in children with primary nephrotic syndrome: case series and literature review

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