-
Microorganisms Apr 2020Human cytomegalovirus (HCMV) expresses a variety of viral regulatory proteins that undergo close interaction with host factors including viral-cellular multiprotein... (Review)
Review
Human cytomegalovirus (HCMV) expresses a variety of viral regulatory proteins that undergo close interaction with host factors including viral-cellular multiprotein complexes. The HCMV protein kinase pUL97 represents a viral cyclin-dependent kinase ortholog (vCDK) that determines the efficiency of HCMV replication via phosphorylation of viral and cellular substrates. A hierarchy of functional importance of individual pUL97-mediated phosphorylation events has been discussed; however, the most pronounced pUL97-dependent phenotype could be assigned to viral nuclear egress, as illustrated by deletion of the UL97 gene or pharmacological pUL97 inhibition. Despite earlier data pointing to a cyclin-independent functionality, experimental evidence increasingly emphasized the role of pUL97-cyclin complexes. Consequently, the knowledge about pUL97 involvement in host interaction, viral nuclear egress and additional replicative steps led to the postulation of pUL97 as an antiviral target. Indeed, validation experiments in vitro and in vivo confirmed the sustainability of this approach. Consequently, current investigations of pUL97 in antiviral treatment go beyond the known pUL97-mediated ganciclovir prodrug activation and henceforward include pUL97-specific kinase inhibitors. Among a number of interesting small molecules analyzed in experimental and preclinical stages, maribavir is presently investigated in clinical studies and, in the near future, might represent a first kinase inhibitor applied in the field of antiviral therapy.
PubMed: 32260430
DOI: 10.3390/microorganisms8040515 -
The Journal of Infectious Diseases Mar 2020This review focuses on recent advances in the field of cytomegalovirus (CMV). The 2 main strategies for CMV prevention are prophylaxis and preemptive therapy.... (Review)
Review
This review focuses on recent advances in the field of cytomegalovirus (CMV). The 2 main strategies for CMV prevention are prophylaxis and preemptive therapy. Prophylaxis effectively prevents CMV infection after solid organ transplantation (SOT) but is associated with high rates of neutropenia and delayed-onset postprophylaxis disease. In contrast, preemptive therapy has the advantage of leading to lower rates of CMV disease and robust humoral and T-cell responses. It is widely used in hematopoietic cell transplant recipients but is infrequently utilized after SOT due to logistical considerations, though these may be overcome by novel methods to monitor CMV viremia using self-testing platforms. We review recent developments in CMV immune monitoring, vaccination, and monoclonal antibodies, all of which have the potential to become part of integrated strategies that rely on viral load monitoring and immune responses. We discuss novel therapeutic options for drug-resistant or refractory CMV infection, including maribavir, letermovir, and adoptive T-cell transfer. We also explore the role of donor factors in transmitting CMV after SOT. Finally, we propose a framework with which to approach CMV prevention in the foreseeable future.
Topics: Antiviral Agents; Clinical Decision-Making; Cytomegalovirus; Cytomegalovirus Infections; Disease Management; Disease Susceptibility; Hematopoietic Stem Cell Transplantation; Humans; Neutropenia; Organ Transplantation; Pre-Exposure Prophylaxis; Time Factors; Tissue Donors; Transplant Recipients; Viral Vaccines
PubMed: 32134486
DOI: 10.1093/infdis/jiz454 -
The Journal of Infectious Diseases Mar 2020The development of therapeutics for cytomegalovirus (CMV) infections, while progressing, has not matched the pace of new treatments of human immunodeficiency virus (HIV)... (Review)
Review
The development of therapeutics for cytomegalovirus (CMV) infections, while progressing, has not matched the pace of new treatments of human immunodeficiency virus (HIV) infections; nevertheless, recent developments in the treatment of CMV infections have resulted in improved human health and perhaps will encourage the development of new therapeutic approaches. First, the deployment of ganciclovir and valganciclovir for both the prevention and treatment of CMV infections and disease in transplant recipients has been further improved with the licensure of the efficacious and less toxic letermovir. Regardless, late-onset CMV disease, specifically pneumonia, remains problematic. Second, the treatment of congenital CMV infections with valganciclovir has beneficially improved both hearing and neurologic outcomes, both fundamental advances for these children. In these pediatric studies, viral load was decreased but not eliminated. Thus, an important lesson learned from studies in both populations is the need for new antiviral agents and the necessity for combination therapies as has been shown to be beneficial in the treatment of HIV infections, among others. The development of monoclonal antibodies, sirtuins, and cyclopropovir may provide new treatment options.
Topics: Acetates; Antiviral Agents; Biomarkers; Clinical Studies as Topic; Cytomegalovirus; Cytomegalovirus Infections; Drug Development; Drug Resistance, Viral; Humans; Infectious Disease Transmission, Vertical; Quinazolines; Research Design; Sirtuins; Stem Cell Transplantation; Treatment Outcome; Viral Load
PubMed: 32134483
DOI: 10.1093/infdis/jiz493 -
Current Hematologic Malignancy Reports Apr 2020CMV DNA polymerase inhibitors such as ganciclovir and foscarnet have dramatically reduced the burden of CMV infection in the HCT recipient. However, their use is often... (Review)
Review
PURPOSE OF REVIEW
CMV DNA polymerase inhibitors such as ganciclovir and foscarnet have dramatically reduced the burden of CMV infection in the HCT recipient. However, their use is often limited by toxicities and resistance. Agents with novel mechanisms and favorable toxicity profiles are critically needed. We review recent developments in CMV antivirals and immune-based approaches to mitigating CMV infection.
RECENT FINDINGS
Letermovir, an inhibitor of the CMV terminase complex, was approved in 2017 for primary CMV prophylaxis in adult seropositive allogeneic HCT recipients. Maribavir, an inhibitor of the CMV UL97 kinase, is currently in two phase 3 treatment studies. Adoptive immunotherapy using third-party T cells has proven safe and effective in preliminary studies. Vaccine development continues, with several promising candidates currently under study. No longer limited to DNA polymerase inhibitors, the prevention and treatment of CMV infections in the HCT recipient is a rapidly evolving field which should translate into improvements in CMV-related outcomes.
Topics: Animals; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Drug Resistance, Viral; Foscarnet; Ganciclovir; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Immunotherapy; Immunotherapy, Adoptive; Molecular Targeted Therapy; Opportunistic Infections; Risk Factors; T-Lymphocytes; Treatment Outcome
PubMed: 31981100
DOI: 10.1007/s11899-020-00557-6 -
Antiviral Research Apr 2020Cytomegalovirus (CMV) drug resistance mutation maps are updated with recent information for polymerase inhibitors, the terminase inhibitor letermovir and the UL97 kinase... (Review)
Review
Cytomegalovirus (CMV) drug resistance mutation maps are updated with recent information for polymerase inhibitors, the terminase inhibitor letermovir and the UL97 kinase inhibitor maribavir. Newly mapped mutations and their phenotypes provide more detail on cross-resistance properties and suggest the need to expand the CMV gene regions covered in diagnostic testing. Next-generation deep sequencing technology offers a more sensitive, higher resolution view of emerging antiviral resistance and is recommended for use in clinical trials. Issues of standardization and diagnostic utility in comparison with traditional Sanger sequencing remain unresolved. Quality control is important for the accurate and reproducible detection of mutant viral populations in clinical specimens.
Topics: Antiviral Agents; Clinical Trials as Topic; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Multiple, Viral; Genotype; Genotyping Techniques; High-Throughput Nucleotide Sequencing; Humans; Mutation; Viral Proteins
PubMed: 31940472
DOI: 10.1016/j.antiviral.2020.104711 -
Current Infectious Disease Reports Nov 2019Transplant recipients are at risk for cytomegalovirus (CMV) infection and associated morbidity and mortality. We summarize recently introduced or currently investigated... (Review)
Review
PURPOSE OF REVIEW
Transplant recipients are at risk for cytomegalovirus (CMV) infection and associated morbidity and mortality. We summarize recently introduced or currently investigated modalities for prevention and treatment of CMV infection in hematopoietic cell (HCT) and solid organ transplant (SOT) recipients.
RECENT FINDINGS
Letermovir was recently approved for CMV prevention in HCT recipients. Data from real world studies support its role to improve outcomes in this population. Letermovir is currently under investigation for broader patient populations and indications. Maribavir is in late stages of development for CMV treatment and may provide a safer alternative to currently available anti-CMV drugs. Promising CMV vaccine candidates and adoptive cell therapy approaches are under evaluation. CMV immune monitoring assays are predicted to play a more central role in our clinical decision making. In recent years, major advances have been made in CMV prevention and treatment in transplant recipients. Rigorous research is ongoing and is anticipated to further impact our ability to improve outcomes in this population.
PubMed: 31732823
DOI: 10.1007/s11908-019-0699-0 -
Antiviral Research Dec 2019In a Phase 2 clinical trial, 120 subjects with cytomegalovirus (CMV) infection refractory or resistant to standard therapy were randomized equally to 3 doses of oral... (Randomized Controlled Trial)
Randomized Controlled Trial
In a Phase 2 clinical trial, 120 subjects with cytomegalovirus (CMV) infection refractory or resistant to standard therapy were randomized equally to 3 doses of oral maribavir treatment, and 70% achieved undetectable plasma CMV DNA within 12 weeks. At study entry, standard diagnostic UL97 genotyping was available for 71 subjects, with 60 (85%) revealing well-characterized ganciclovir resistance mutations that did not preclude a therapeutic response to maribavir. Central laboratory testing of a range of UL97 codons (288-468) not fully covered by standard genotyping was done on 93 subjects at baseline. This detected no previously known maribavir resistance mutations, but identified atypical mutations in 3 subjects, including a P-loop substitution F342Y, and ATP-binding region substitutions K359E/Q. By recombinant phenotyping, K359E and K359Q each conferred a nearly 4-fold increased ganciclovir 50% inhibitory concentration (EC50) without maribavir resistance, whereas F342Y conferred a 6-fold increased ganciclovir EC50 and a 4.5-fold increased maribavir EC50. The subject with F342Y detected at baseline did not achieve plasma CMV DNA clearance after 12 weeks of maribavir therapy and later developed an additional UL97 substitution H411Y known to confer 12- to 20-fold increased MBV EC50 by itself. The combination of F342Y and H411Y was shown to increase the maribavir EC50 by 56-fold. Diagnostic genotyping of UL97 should be expanded to cover the ATP-binding region beginning at codon 335 to enable the detection of atypical resistance mutations and further correlation of their clinical significance.
Topics: Benzimidazoles; Cell Line; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Ganciclovir; Genes, Viral; Genotyping Techniques; Humans; Inhibitory Concentration 50; Mutation; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides
PubMed: 31568799
DOI: 10.1016/j.antiviral.2019.104616 -
Journal of Clinical Pharmacology Jan 2020Maribavir is an investigational drug being evaluated in transplant recipients with cytomegalovirus infection. To understand potential drug-drug interactions, we examined...
Maribavir is an investigational drug being evaluated in transplant recipients with cytomegalovirus infection. To understand potential drug-drug interactions, we examined the effects of multiple doses of maribavir on cytochrome P450 (CYP) 2D6 and P-glycoprotein (P-gp) activity using probe substrates in healthy volunteers. During this phase 1 open-label study (NCT02775240), participants received the probe substrates digoxin (0.5 mg) and dextromethorphan (30 mg) before and after maribavir (400 mg twice daily for 8 days). Serial plasma samples were analyzed for digoxin, dextromethorpha, dextrorphan, and maribavir concentrations. Pharmacokinetic parameters were calculated (noncompartmental analysis) and analyzed with a linear mixed-effects model for treatment comparison to estimate geometric mean ratios (GMRs) and 90% confidence intervals (CIs). CYP2D6 polymorphisms were genotyped using polymerase chain reaction. Overall, 17 of 18 participants (94.4%) completed the study. All participants were genotyped as CYP2D6 intermediate/extensive metabolizers. GMR (90%CI) of digoxin C , AUC , and AUC with and without maribavir was 1.257 (1.139-1.387), 1.187 (1.088-1.296), and 1.217 (1.110-1.335), respectively, outside the "no-effect" window (0.8-1.25). GMR (90%CI) of dextromethorphan AUC and AUC ratio of dextromethorphan/dextrorphan were 0.877 (0.692-1.112) and 0.901 (0.717-1.133), respectively, marginally outside the no-effect window, although large variability was observed in these pharmacokinetic parameters. Pharmacokinetic parameters of dextrorphan were unaffected. Maribavir inhibited P-gp activity but did not affect CYP2D6 activity. Maribavir's effect on the pharmacokinetics of P-gp substrates should be evaluated individually, and caution should be exercised with P-gp substrates with narrow therapeutic windows.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adult; Antiviral Agents; Benzimidazoles; Cytochrome P-450 CYP2D6; Cytomegalovirus Infections; Dextromethorphan; Digoxin; Drug Interactions; Female; Genotype; Healthy Volunteers; Humans; Male; Middle Aged; Ribonucleosides; Young Adult
PubMed: 31385617
DOI: 10.1002/jcph.1504 -
Journal of Virology Sep 2019The herpesvirus human cytomegalovirus (HCMV) is a leading cause of congenital birth defects. Infection can result in infants born with a variety of symptoms, including...
The herpesvirus human cytomegalovirus (HCMV) is a leading cause of congenital birth defects. Infection can result in infants born with a variety of symptoms, including hepatosplenomegaly, microcephaly, and developmental disabilities. Microcephaly is associated with disruptions in the neural progenitor cell (NPC) population. Here, we defined the impact of HCMV infection on neural tissue development and calcium regulation, a critical activity in neural development. Regulation of intracellular calcium involves purinergic receptors and voltage-gated calcium channels (VGCC). HCMV infection compromised the ability of both pathways in NPCs as well as fibroblasts to respond to stimulation. We observed significant drops in basal calcium levels in infected NPCs which were accompanied by loss in VGCC activity and purinergic receptor responses. However, uninfected cells in the population retained responsiveness. Addition of the HCMV inhibitor maribavir reduced viral spread but failed to restore activity in infected cells. To study neural development, we infected three-dimensional cortical organoids with HCMV. Infection spread to a subset of cells over time and disrupted organoid structure, with alterations in developmental and neural layering markers. Organoid-derived infected neurons and astrocytes were unable to respond to stimulation whereas uninfected cells retained nearly normal responses. Maribavir partially restored structural features, including neural rosette formation, and dampened the impact of infection on neural cellular function. Using a tissue model system, we have demonstrated that HCMV alters cortical neural layering and disrupts calcium regulation in infected cells. Human cytomegalovirus (HCMV) replicates in several cell types throughout the body, causing disease in the absence of an effective immune response. Studies on HCMV require cultured human cells and tissues due to species specificity. In these studies, we investigated the impact of infection on developing three-dimensional cortical organoid tissues, with specific emphasis on cell-type-dependent calcium signaling. Calcium signaling is an essential function during neural differentiation and cortical development. We observed that HCMV infects and spreads within these tissues, ultimately disrupting cortical structure. Infected cells exhibited depleted calcium stores and loss of ATP- and KCl-stimulated calcium signaling while uninfected cells in the population maintained nearly normal responses. Some protection was provided by the viral inhibitor maribavir. Overall, our studies provide new insights into the impact of HCMV on cortical tissue development and function.
Topics: Benzimidazoles; Calcium Signaling; Cell Differentiation; Cell Line; Cytomegalovirus; Cytomegalovirus Infections; Humans; Induced Pluripotent Stem Cells; Neural Stem Cells; Organ Culture Techniques; Organoids; Receptors, Purinergic; Ribonucleosides; Virus Replication; Voltage-Gated Sodium Channels
PubMed: 31217241
DOI: 10.1128/JVI.00954-19 -
Antiviral Research Mar 2019Double-stranded (ds) DNA virus infections often occur concomitantly in immunocompromised patients. We performed a systematic search of published in vitro activity for... (Comparative Study)
Comparative Study
BACKGROUND
Double-stranded (ds) DNA virus infections often occur concomitantly in immunocompromised patients. We performed a systematic search of published in vitro activity for nine approved and investigational antivirals to understand the spectrum of in vitro activity against dsDNA viruses.
METHODS
A literature search was performed (PubMed and the WoS Core Collection) using keywords related to: 1) targeted approved/developmental antivirals (acyclovir, artesunate, brincidofovir, cidofovir, cyclopropavir (filociclovir), foscarnet, ganciclovir, letermovir, and maribavir); 2) pathogenic dsDNA viruses; 3) in vitro activity. We summarized data from 210 publications.
RESULTS
Activity against ≤3 viruses was documented for maribavir (cytomegalovirus, Epstein-Barr virus), and letermovir, while activity against > 3 viruses was shown for ganciclovir, cidofovir, acyclovir, foscarnet, cyclopropavir, artesunate, and brincidofovir. The EC values of brincidofovir were the lowest, ranging from 0.001 to 0.27 μM, for all viruses except papillomaviruses. The next most potent agents included cidofovir, ganciclovir, foscarnet, and acyclovir with EC values between 0.1 μM and >10 μM for cytomegalovirus, herpes simplex virus, and adenovirus.
CONCLUSION
Most of the identified antivirals had in vitro activity against more than one dsDNA virus. Brincidofovir and cidofovir have broad-spectrum activity, and brincidofovir has the lowest EC values. These findings could assist clinical practice and developmental research.
Topics: Antiviral Agents; DNA Viruses; DNA, Viral; Drug Resistance, Viral; Drugs, Investigational; Humans
PubMed: 30677427
DOI: 10.1016/j.antiviral.2019.01.008