Treatment and Prevention of CMV Disease in Transplant Recipients: Current Knowledge and Future Perspectives

Hodowanec, Aimee C.; Pikis, Andreas; Komatsu, Takashi; Sampson, Mario R.; Younis, Islam R.; O’Rear, Julian J.; Singer, Mary E.

doi:10.1002/jcph.1363

Cited by 9 publications

(7 citation statements)

References 121 publications

(239 reference statements)

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“…However, HCMV can acquire Letermovir resistance in vitro [31] and in patients [32]. The resistance was associated with mutations in UL56 and to lesser extend in UL89 or UL51 [33,34]. Due to these limitations, we are convinced that additional treatment options and drug targets are urgently needed.…”

Section: The Human Cytomegalovirusmentioning

confidence: 99%

Cellular Cullin RING Ubiquitin Ligases: Druggable Host Dependency Factors of Cytomegaloviruses

Becker

Le‐Trilling

Trilling

2019

IJMS

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Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that frequently causes morbidity and mortality in individuals with insufficient immunity, such as transplant recipients, AIDS patients, and congenitally infected newborns. Several antiviral drugs are approved to treat HCMV infections. However, resistant HCMV mutants can arise in patients receiving long-term therapy. Additionally, side effects and the risk to cause birth defects limit the use of currently approved antivirals against HCMV. Therefore, the identification of new drug targets is of clinical relevance. Recent work identified DNA-damage binding protein 1 (DDB1) and the family of the cellular cullin (Cul) RING ubiquitin (Ub) ligases (CRLs) as host-derived factors that are relevant for the replication of human and mouse cytomegaloviruses. The first-in-class CRL inhibitory compound Pevonedistat (also called MLN4924) is currently under investigation as an anti-tumor drug in several clinical trials. Cytomegaloviruses exploit CRLs to regulate the abundance of viral proteins, and to induce the proteasomal degradation of host restriction factors involved in innate and intrinsic immunity. Accordingly, pharmacological blockade of CRL activity diminishes viral replication in cell culture. In this review, we summarize the current knowledge concerning the relevance of DDB1 and CRLs during cytomegalovirus replication and discuss chances and drawbacks of CRL inhibitory drugs as potential antiviral treatment against HCMV.

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Section: The Human Cytomegalovirusmentioning

confidence: 99%

Cellular Cullin RING Ubiquitin Ligases: Druggable Host Dependency Factors of Cytomegaloviruses

Becker

Le‐Trilling

Trilling

2019

IJMS

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“…For cases who were detected Cytomegalovirus 22 and Human gammaherpesvirus 4 23 by mNGS, if serum PCR indicated positive at the same time, we identified that they were infectious pathogens. Furthermore, the mixed infection was defined as the isolation of more than one pathogenic species.…”

Section: Methodsmentioning

confidence: 99%

The Performance of Metagenomic Next-Generation Sequence in the Diagnosis of Suspected Opportunistic Infections in Patients with Acquired Immunodeficiency Syndrome

Liu¹,

Yuan²,

Sun³

et al. 2022

IDR

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Background For acquired immunodeficiency syndrome (AIDS) patients with suspected opportunistic infections, the rapid and accurate identification of pathogens remains a challenge. Metagenomic next-generation sequencing (mNGS) has emerged as a pan-pathogen assay for infectious diseases diagnosis, but its guiding significance for diagnosis and antimicrobials treatment in AIDS patients with suspected opportunistic infections is still not well established. In this study, we compared the microbiological diagnostic value of mNGS with that of conventional microbiological tests (CMTs) in AIDS patients with suspected opportunistic infections. Methods From January 2018 to February 2021, a retrospective study was performed at four tertiary teaching hospitals in China and data of 86 AIDS patients with suspected opportunistic infections were collected. The pathogen detection performance of mNGS and CMTs were compared. Results Positive agreement between mNGS and clinical diagnosis was significantly higher than that of CMTs (65/86 (75.6%) vs 37/86 (43.0%)). In addition, mNGS identified more bacterial (25 vs 2), fungal (5 vs 3), viral (9 vs 2) organisms compared with CMTs. Mixed infection were detected in 34 patients by mNGS combined with CMTs. Viruses (94.1%, 32/34) and fungi (94.1%, 32/34) were commonly seen in the mixed infection cases. mNGS helped identify the pathogen or guide appropriate treatment in 49/86 (57%) patients. Meanwhile, CMTs also contributed in the decision of appropriate treatment in 28 patients. The successful de-escalation or discontinuation of treatment was supported in 37 patients with the help of mNGS. We observed a significant reduction in the number of patients being prescribed foscarnet (52.3% vs 23.26%, p < 0.001), moxifloxacin (34.9% vs 10.5%, p = 0.005), and levofloxacin (32.6% vs 14%, p = 0.001) before and after mNGS. Conclusion For AIDS patients with suspected opportunistic infections, mNGS can provide early, noninvasive, and rapid microbiological diagnosis. mNGS may lead to a more precise antimicrobial treatment and reduced the unreasonable use of antimicrobials.

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“…Because of the non-specificity of clinical symptoms caused by CMV infection, laboratory examination is the main basis for the diagnosis of CMV infection. The most two widely used clinical methods are CMV virus replication and serum immunological methods including the detection of CMV IgG, CMV IgM and CMV antigen PP65 (2) In patients with impaired immune function, the production of CMV antibody is weakened or delayed, which may lead to false negative and increase the rate of missed diagnosis, therefor PCR detection of CMV-DNA has largely become the standard method for diagnosis of CMV infection and monitoring of treatment (3). Daisuke Mizushima et al reported that plasma CMV-DNA PCR has important value in the diagnosis for both CMV retinitis and all CMV-EOD in patients with advanced HIV-1 infection (4).…”

Section: Introductionmentioning

confidence: 99%

Cytomegalovirus (CMV) infection in HIV/AIDS patients and diagnostic values of CMV-DNA detection across different sample types

Zhao

Zhuo

et al. 2020

Ann Palliat Med

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Background: Cytomegalovirus (CMV) is a common herpesvirus that has spread throughout the human population. It can easily cause organ damage in individuals who are immunocompromised. While many studies have examined the virology and immunology of simple CMV infection, few articles have described the unique immunological features of patients with HIV-CMV coinfection.Methods: CMV infection was detected in 808 HIV/AIDS inpatients in our center from January 2017 to October 2019, and the relevant data from these patients were retrospectively analyzed. HIV-RNA, CD4+T lymphocyte count, CMV-DNA, and related antibodies were measured in all patients. The positive rates of CMV-DNA in blood, urine, and cerebrospinal fluid (CSF) were compared. The positive rates between anti-CMV-immunoglobulin M (IgM) antibody and CMV-DNA in blood were compared. The correlation between immune status and CMV positive rate was analyzed based on the CD4+ T lymphocyte count. Results:The overall positive rate of CMV infection in HIV/AIDS patients was 29.05%. The positive rate of CMV-DNA in urine, blood, and CSF samples was 25.27%, 26.01%, and 5.70%, respectively, and showed no significant difference between urine and blood. However, plasma CMV-IgM antibody level was significantly different between the urine and blood. The absolute CD4+ T lymphocyte count and the HIV-RNA level were significantly different between the CMV-infected group and the non-CMV infected group.Conclusions: Low CD4+ T lymphocyte count and high HIV-1 viral load are risk factors for CMV infection in HIV/AIDS patients. Detection of urine or plasma CMV-DNA by using real-time fluorescence quantitative polymerase chain reaction (PCR) is highly valuable in screening CMV infection in HIV/AIDS patients, while detection of blood CMV IgG and CMV IgM levels has limited clinical value.

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Treatment and Prevention of CMV Disease in Transplant Recipients: Current Knowledge and Future Perspectives

Cited by 9 publications

References 121 publications

Cellular Cullin RING Ubiquitin Ligases: Druggable Host Dependency Factors of Cytomegaloviruses

Cellular Cullin RING Ubiquitin Ligases: Druggable Host Dependency Factors of Cytomegaloviruses

The Performance of Metagenomic Next-Generation Sequence in the Diagnosis of Suspected Opportunistic Infections in Patients with Acquired Immunodeficiency Syndrome

Cytomegalovirus (CMV) infection in HIV/AIDS patients and diagnostic values of CMV-DNA detection across different sample types

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