-
The Journal of Biological Chemistry Nov 2022The human cytomegalovirus (HCMV) UL97 protein is a conserved herpesvirus protein kinase (CHPK) and a viral cyclin-dependent kinase (v-CDK). However, mechanisms...
The human cytomegalovirus (HCMV) UL97 protein is a conserved herpesvirus protein kinase (CHPK) and a viral cyclin-dependent kinase (v-CDK). However, mechanisms regulating its activity in the context of infection are unknown. Here, we identified several cellular regulatory 14-3-3 proteins as UL97-interacting partners that promote UL97 stability. Humans are known to encode seven isoforms of 14-3-3 proteins (β, ε, η, γ, σ, θ, and ζ) that bind phosphoserines or phosphothreonines to impact protein structure, stability, activity, and localization. Our proteomic analysis of UL97 identified 49 interacting partners, including 14-3-3 isoforms β, η, and γ. Furthermore, coimmunoprecipitation with Western blotting assays demonstrated that UL97 interaction with 14-3-3 isoforms β, ε, η, γ, and θ occurs in a kinase activity-dependent manner. Using mutational analysis, we determined the serine residue at amino acid 13 of UL97 is crucial for 14-3-3 interaction. We demonstrate UL97 S13A (serine to alanine substitution at residue 13) retains kinase activity but the mutant protein accumulated at lower levels than WT UL97. Finally, we show both laboratory (AD169) and clinical (TB40/E) strains of HCMV encoding UL97 S13A replicated with WT kinetics in fibroblasts but showed decreased UL97 accumulation. Taken together, we conclude that 14-3-3 proteins interact with and stabilize UL97 during HCMV infection.
Topics: Humans; Cytomegalovirus; 14-3-3 Proteins; Cyclin-Dependent Kinases; Serine; Proteomics; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 36150501
DOI: 10.1016/j.jbc.2022.102513 -
Journal of Clinical Pharmacology Feb 2023Maribavir, an orally bioavailable antiviral, has shown superior activity against posttransplant cytomegalovirus infection compared with conventional antivirals. It is... (Randomized Controlled Trial)
Randomized Controlled Trial
Maribavir, an orally bioavailable antiviral, has shown superior activity against posttransplant cytomegalovirus infection compared with conventional antivirals. It is primarily metabolized in the liver. This open-label, single-center study evaluated the effect of hepatic impairment on the pharmacokinetics of maribavir in nontransplant participants. A single 200-mg dose of maribavir was administered orally under fasting conditions to participants with moderate hepatic impairment (Child-Pugh class B) (n = 10) and healthy controls (n = 10) matched for age, weight, sex, and smoking status. Compared with participants with normal hepatic function, maximum plasma concentration (C ) and area under the plasma concentration-time curve (AUC) from time 0 to infinity values for maribavir in participants with moderate hepatic impairment were 1.346-fold (90%CI of geometric mean ratio, 1.091-1.660) and 1.261-fold (0.889-1.787) higher, respectively. However, C and AUC values for unbound maribavir were comparable. For VP 44469, the main metabolite of maribavir, the C and AUC from time 0 to infinity values were 1.190-fold (0.836-1.693) and 1.309-fold (1.007-1.702) higher, respectively, in participants with moderate hepatic impairment. In total, 7 mild treatment-emergent adverse events were reported, all in the moderate hepatic impairment group. Dysgeusia was the most frequently reported treatment-emergent adverse event, at a frequency of 50%. These results indicated that total maribavir concentrations were mildly increased in participants with moderate hepatic impairment, while unbound concentrations were unaffected. Similar maribavir pharmacokinetics in participants with moderate hepatic impairment and normal hepatic function suggest that dose adjustment may not be required for patients with moderate hepatic impairment.
Topics: Humans; Area Under Curve; Liver Diseases; Benzimidazoles; Ribonucleosides
PubMed: 36089648
DOI: 10.1002/jcph.2155 -
The Annals of Pharmacotherapy May 2023To review the efficacy and safety of maribavir for management of cytomegalovirus (CMV) in solid organ transplant recipients. (Review)
Review
OBJECTIVE
To review the efficacy and safety of maribavir for management of cytomegalovirus (CMV) in solid organ transplant recipients.
DATA SOURCES
A literature search of PubMed and the Cochrane Controlled Trials Register (1960 to early July 2022) was performed using the following search terms: , and .
STUDY SELECTION AND DATA EXTRACTION
All relevant English-language studies were reviewed and considered, with a focus on phase 3 trials.
DATA SYNTHESIS
Maribavir, an orally available benzimidazole riboside with minimal adverse effects, was originally studied for universal prophylaxis in phase 3 trials but failed to demonstrate noninferiority over placebo and oral ganciclovir. It was effective for preemptive treatment in a dose-finding Phase 2 study. Maribavir is FDA approved for treatment of refractory/resistant CMV infection based on improved response rate at 8 weeks compared with investigator-assigned therapy (IAT) when initiated at median viral loads less than approximately 10 000 IU/mL (55.7% vs 23.9%, < 0.001). Recurrence after 8-week treatment for refractory/resistant CMV was high (maribavir 50% vs IAT 39%). Significant drug interactions exist and must be managed by a pharmacotherapy expert to prevent harm.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
The addition of maribavir to the antiviral armamentarium should improve the management of refractory/resistant CMV, allowing early transition from toxic, high-cost, intravenous agents such as foscarnet and outpatient management. Optimal timing of initiation, duration, and potential alternative uses are unclear.
CONCLUSION
Future studies are needed to fully elucidate the role of maribavir in the management of CMV after transplant.
Topics: Adult; Humans; Cytomegalovirus; Transplant Recipients; Antiviral Agents; Cytomegalovirus Infections; Ganciclovir; Benzimidazoles
PubMed: 36003036
DOI: 10.1177/10600280221118959 -
Antimicrobial Agents and Chemotherapy Sep 2022Maribavir was approved by the U.S. Food and Drug Administration in November 2021 for the treatment of adult and pediatric patients with post-transplant cytomegalovirus... (Review)
Review
Maribavir was approved by the U.S. Food and Drug Administration in November 2021 for the treatment of adult and pediatric patients with post-transplant cytomegalovirus (CMV) infection/disease that is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir, or foscarnet. Maribavir is an oral benzimidazole riboside with potent and selective multimodal anti-CMV activity. It utilizes a novel mechanism of action which confers activity against CMV strains that are resistant to traditional anti-CMV agents, and also offers a more favorable safety profile relative to the dose-limiting side effects of previously available therapies. Maribavir was initially studied as an agent for CMV prophylaxis in solid organ and hematopoietic stem cell recipients, but initial phase III trials failed to meet clinical efficacy endpoints. It has been more recently studied as a therapeutic agent at higher doses for refractory-resistant (R-R) CMV infections with favorable outcomes. After an overview of maribavir's chemistry and clinical pharmacology, this review will summarize clinical efficacy, safety, tolerability, and resistance data associated with maribavir therapy.
Topics: Adult; Anti-Infective Agents; Antiviral Agents; Benzimidazoles; Child; Cidofovir; Cytomegalovirus Infections; Dichlororibofuranosylbenzimidazole; Drug Resistance, Viral; Foscarnet; Ganciclovir; Humans; Valganciclovir
PubMed: 35916518
DOI: 10.1128/aac.02405-21 -
Clinical Microbiology and Infection :... Jan 2023The burden that cytomegalovirus (CMV) portends for haematopoietic and solid-organ transplant recipients cannot be understated. Valganciclovir and ganciclovir have... (Review)
Review
BACKGROUND
The burden that cytomegalovirus (CMV) portends for haematopoietic and solid-organ transplant recipients cannot be understated. Valganciclovir and ganciclovir have successfully been used for prevention and treatment of CMV infections, although with serious side effects such as leucopenia and some development of resistance. Until recently, available therapies for ganciclovir-resistant CMV have significant toxicities. Although advances have been made in the field, the unmet medical needs for effective and well-tolerated therapies are significant.
OBJECTIVES
This review aims to summarise the current and emerging CMV antiviral drugs and discusses future perspectives in the field.
SOURCES
We searched for relevant articles with pertinent keywords: "Cytomegalovirus OR CMV", "Transplant" and "Antiviral". Articles published after 2019 were given preference. Articles were reviewed by the authors for relevance and impact to the subject of interest.
CONTENT
We outline in this review current advances in prophylaxis of CMV infection with letermovir, breakthrough CMV infections while on or after prophylaxis, the development of resistant and refractory CMV infections, and the newly approved anti-CMV agent, maribavir, in haematopoietic and solid-organ transplant recipients.
IMPLICATIONS
Prevention of CMV infections after transplant has improved greatly over the past few years. Despite major advancements, breakthrough CMV infections and development of refractory and resistant CMV infections remain major complications post transplantation. We highlight emerging therapeutics that tolerably and effectively prevent and treat CMV infections, especially refractory and resistant cases.
Topics: Humans; Transplant Recipients; Cytomegalovirus Infections; Antiviral Agents; Ganciclovir; Cytomegalovirus
PubMed: 35843567
DOI: 10.1016/j.cmi.2022.07.001 -
Clinical Infectious Diseases : An... Feb 2023The immune response to COVID-19 vaccination is inferior in kidney transplant recipients (KTRs) and to a lesser extent in patients on dialysis or with chronic kidney... (Clinical Trial)
Clinical Trial
Antibody and T-Cell Responses 6 Months After Coronavirus Disease 2019 Messenger RNA-1273 Vaccination in Patients With Chronic Kidney Disease, on Dialysis, or Living With a Kidney Transplant.
BACKGROUND
The immune response to COVID-19 vaccination is inferior in kidney transplant recipients (KTRs) and to a lesser extent in patients on dialysis or with chronic kidney disease (CKD). We assessed the immune response 6 months after mRNA-1273 vaccination in kidney patients and compared this to controls.
METHODS
A total of 152 participants with CKD stages G4/5 (eGFR <30 mL/min/1.73 m2), 145 participants on dialysis, 267 KTRs, and 181 controls were included. SARS-CoV-2 Spike S1 specific IgG antibodies were measured using fluorescent bead-based multiplex-immunoassay, neutralizing antibodies to ancestral, Delta, and Omicron (BA.1) variants by plaque reduction, and T-cell responses by interferon-γ release assay.
RESULTS
At 6 months after vaccination, S1-specific antibodies were detected in 100% of controls, 98.7% of CKD G4/5 patients, 95.1% of dialysis patients, and 56.6% of KTRs. These figures were comparable to the response rates at 28 days, but antibody levels waned significantly. Neutralization of the ancestral and Delta variants was detected in most participants, whereas neutralization of Omicron was mostly absent. S-specific T-cell responses were detected at 6 months in 75.0% of controls, 69.4% of CKD G4/5 patients, 52.6% of dialysis patients, and 12.9% of KTRs. T-cell responses at 6 months were significantly lower than responses at 28 days.
CONCLUSIONS
Although seropositivity rates at 6 months were comparable to rates at 28 days after vaccination, significantly decreased antibody levels and T-cell responses were observed. The combination of low antibody levels, reduced T-cell responses, and absent neutralization of the newly emerging variants indicates the need for additional boosts or alternative vaccination strategies in KTRs.
CLINICAL TRIALS REGISTRATION
NCT04741386.
Topics: Humans; Antibodies, Neutralizing; Antibodies, Viral; COVID-19; COVID-19 Vaccines; Immunoglobulin G; Kidney Transplantation; Renal Dialysis; Renal Insufficiency, Chronic; SARS-CoV-2; T-Lymphocytes; Vaccination
PubMed: 35796536
DOI: 10.1093/cid/ciac557 -
Transplant Infectious Disease : An... Aug 2022
Topics: Benzimidazoles; Dichlororibofuranosylbenzimidazole; Humans; Immunosuppressive Agents; Organ Transplantation; Ribonucleosides; Tacrolimus; Transplant Recipients
PubMed: 35598322
DOI: 10.1111/tid.13869 -
Antiviral Research Jun 2022Letermovir (LTV) is approved for the prophylaxis of human cytomegalovirus (HCMV) infection in adult seropositive recipients of an allogeneic hematopoietic stem cell...
Letermovir (LTV) is approved for the prophylaxis of human cytomegalovirus (HCMV) infection in adult seropositive recipients of an allogeneic hematopoietic stem cell transplant. Here, we report on the in vitro activity of LTV against a large panel of clinical HCMV isolates and recombinant viruses with different drug susceptibility phenotypes to currently-approved DNA polymerase inhibitors or maribavir. No pre-existing mutations conferring resistance to LTV were detected by Sanger sequencing in clinical HCMV isolates susceptible or resistant to DNA polymerases inhibitors. The susceptibility of LTV against the different recombinant HCMV mutants with amino acid substitutions in the UL97 kinase or in the UL54 DNA polymerase was similar to that of the wild type virus. LTV was also effective against recombinant HCMV harboring UL97 mutations conferring resistance to maribavir.
Topics: Acetates; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Ganciclovir; Humans; Mutation; Phenotype; Quinazolines
PubMed: 35490740
DOI: 10.1016/j.antiviral.2022.105328 -
Antiviral Therapy Nov 2021Human cytomegalovirus (HCMV) is involved in complications on immunocompromised patients. Current therapeutics are associated with several drawbacks, such as...
BACKGROUND
Human cytomegalovirus (HCMV) is involved in complications on immunocompromised patients. Current therapeutics are associated with several drawbacks, such as nephrotoxicity.
PURPOSE
As HCMV infection affects inflammation pathways, especially prostaglandin E2 (PGE2) production via cyclooxygenase 2 enzyme (COX-2), we designed 2'-hydroxychalcone compounds to inhibit human cytomegalovirus.
STUDY DESIGN
We first selected the most efficient new synthetic chalcones for their effect against COX-2-catalyzed PGE2.
STUDY SAMPLE
Among the selected compounds, we assessed the antiviral efficacy against different HCMV strains, such as the laboratory strain AD169 and clinical strains (naïve or multi-resistant to conventional drugs) and toxicity on human cells.
RESULTS
The most efficient and less toxic compound (chalcone 7) was tested against HCMV in combination with other antiviral molecules: artesunate (ART), baicalein (BAI), maribavir (MBV), ganciclovir (GCV), and quercetin (QUER) using Compusyn software. Association of chalcone 7 with MBV and BAI is synergistic, antagonistic with QUER, and additive with GCV and ART.
CONCLUSION
These results provide a promising search path for potential bitherapies against HCMV.
Topics: Antiviral Agents; Artesunate; Chalcone; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cytomegalovirus; Dinoprostone; Ganciclovir; Humans
PubMed: 35485337
DOI: 10.1177/13596535211064078