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Transplantation and Cellular Therapy Jul 2021Infections due to herpesviruses resistant to first-line antivirals remains an ever-present and serious complication in recipients of hematopoietic cell transplantation... (Observational Study)
Observational Study
Infections due to herpesviruses resistant to first-line antivirals remains an ever-present and serious complication in recipients of hematopoietic cell transplantation (HCT) and other cellular therapies. Foscarnet is the most common therapy for patients who have resistant herpesvirus infections or intolerable cytopenias due to ganciclovir or valganciclovir; however, the widespread use of foscarnet is limited by its associated nephrotoxicity and challenges in administration. In the earliest published small case series investigating the optimal infusion modality, patients with acquired immunodeficiency syndrome (AIDS) due to the human immunodeficiency virus (HIV) received either continuous infusion or intermittent dosing of foscarnet. Moreover, there was no standardization of hydration strategies to minimize side effects. Eventually, intermittent foscarnet infusions became the standard of care; however, the true impact of hydration and infusion duration on nephrotoxicity has not been adequately studied, and the reports of foscarnet administration in HCT patients has been limited primarily to intermittent infusions. In this report, we characterize the administration of foscarnet as a 24-hour continuous infusion in both the inpatient and outpatient settings compared with intermittent infusion in HCT recipients. This retrospective, single-center, observational study at Stanford University Medical Center assessed HCT recipients who received foscarnet between January 2009 and May 2019. Twenty-eight of 45 patients (62.2%) who received continuous-infusion foscarnet experienced an acute kidney injury (AKI) as defined by the Kidney Disease Improving Global Outcomes classification, compared with 39 of 62 patients (62.9%) who received conventional infusion (P = .94). The average duration of outpatient antiviral days for the continuous infusion group was 9 days (range, 0 to 121 days), compared with 6.3 days (range, 0 to 70 days) in the intermittent infusion group (P = .54). Our findings suggest that foscarnet given as a continuous infusion or as an intermittent infusion have similar rates of adverse reactions, most notably similar rates of AKI. Administering foscarnet as a continuous infusion is a feasible option to facilitate outpatient treatment.
Topics: Cytomegalovirus Infections; Foscarnet; Ganciclovir; Hematopoietic Stem Cell Transplantation; Humans; Retrospective Studies
PubMed: 33891883
DOI: 10.1016/j.jtct.2021.03.018 -
Transplantation and Cellular Therapy Jan 2021The high incidence of human herpesvirus-6 (HHV-6) reactivation, potentially interfering with engraftment after umbilical cord blood (UCB) hematopoietic cell...
The high incidence of human herpesvirus-6 (HHV-6) reactivation, potentially interfering with engraftment after umbilical cord blood (UCB) hematopoietic cell transplantation (HCT), remains a major challenge. To potentially address this problem, we evaluated the effect of prophylactic foscarnet administered twice daily beginning on day +7 and continuing through engraftment in 25 patients. To determine the impact of foscarnet on HHV-6, engraftment, and other transplantation outcomes, we compared results in 61 identically treated patients with hematologic malignancies. Treatment and control groups underwent reduced-intensity conditioning UCB HCT with a conditioning regimen of fludarabine, cyclophosphamide, and total body irradiation 200 cGy with or without antithymocyte globulin (ATG), using sirolimus plus mycophenolate mofetil immune suppression. The treatment and control groups were similar in terms of age, disease risk, use of ATG, Hematopoietic Cell Transplantation Comorbidity Index, and graft CD34 cell dose; however, foscarnet-treated patients were less likely to receive a double UCB graft and to be treated more recently (2016 to 2018). The cumulative incidence of HHV-6 reactivation by day +100 was 63% for all patients (95% confidence interval [CI], 51% to 75%) and was not significantly different between the 2 groups. HHV-6 reactivation occurred at a median of 34 days in the foscarnet group and 25.5 days in the control group. The incidence of neutrophil engraftment at day 42 was higher in the foscarnet group compared with the control group (96%; [95% CI, 83% to 100%] versus 75% [95% CI, 64% to 85%]; P< .01). The cumulative incidence of platelet engraftment by 6 months was 92% (95% CI, 69% to 100%) for the foscarnet group versus 75% (95% CI, 60% to 90%) for the control group (P= .08), and multivariate analysis identified the use of foscarnet as an independent predictor of better platelet engraftment. No patients died as a result of graft failure in recipients of foscarnet, whereas 5 patients died from graft failure in the control group. Six-month overall survival (OS) and nonrelapse mortality (NRM) were better in the foscarnet group (96% versus 72% [P= .02] and 4% versus 18% [P= .07], respectively). Even though foscarnet prophylaxis did not prevent HHV-6 viremia, we observed a delay in time to HHV-6 reactivation, a trend toward differences in engraftment, NRM, and OS compared with historical controls.
Topics: Cord Blood Stem Cell Transplantation; Foscarnet; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpesvirus 6, Human; Humans
PubMed: 33053448
DOI: 10.1016/j.bbmt.2020.10.008 -
Retinal Cases & Brief Reports Mar 2024To determine whether maribavir is effective at treating ganciclovir-resistant cytomegalovirus retinitis.
PURPOSE
To determine whether maribavir is effective at treating ganciclovir-resistant cytomegalovirus retinitis.
METHODS
Retrospective case report of a lung-transplant patient with bilateral cytomegalovirus retinitis documented with serum and aqueous humor studies and color fundus photographs.
RESULTS
A 72-year-old lung-transplant patient with active ganciclovir-resistant cytomegalovirus was treated with intravitreal foscarnet therapy in one eye. Retinitis developed in the contralateral eye and was managed with systemic maribavir alone. Active retinitis regressed in both the eye treated with intravitreal foscarnet and the uninjected eye.
CONCLUSION
This patient's results suggest that systemic maribavir is an effective treatment for treatment-resistant cytomegalovirus retinitis.
Topics: Humans; Aged; Cytomegalovirus Retinitis; Valganciclovir; Foscarnet; Retrospective Studies; Ganciclovir; Antiviral Agents; Dichlororibofuranosylbenzimidazole
PubMed: 36730596
DOI: 10.1097/ICB.0000000000001372 -
RSC Advances 2020Adenosine 5'-diphosphate ribose (ADPR) is an intracellular signalling molecule generated from nicotinamide adenine dinucleotide (NAD). Synthetic ADPR analogues can shed...
Adenosine 5'-diphosphate ribose (ADPR) is an intracellular signalling molecule generated from nicotinamide adenine dinucleotide (NAD). Synthetic ADPR analogues can shed light on the mechanism of activation of ADPR targets and their downstream effects. Such chemical biology studies, however, are often challenging due to the negatively charged pyrophosphate, also sensitive to cellular pyrophosphatases, and prior work on an initial ADPR target, the transient receptor potential cation channel TRPM2, showed complete pyrophosphate group replacement to be a step too far in maintaining biological activity. Thus, we designed ADPR analogues with just one of the negatively charged phosphate groups removed, by employing a phosphonoacetate linker. Synthesis of two novel phosphonoacetate ADPR analogues is described tandem -dicyclohexylcarbodiimide coupling to phosphonoacetic acid. Neither analogue, however, showed significant agonist or antagonist activity towards TRPM2, underlining the importance of a complete pyrophosphate motif in activation of this particular receptor.
PubMed: 31934327
DOI: 10.1039/C9RA09284F -
Scientific Reports Jul 2018Aspartate carbamoyltransferase (ATCase) is a large dodecameric enzyme with six active sites that exhibits allostery: its catalytic rate is modulated by the binding of...
Aspartate carbamoyltransferase (ATCase) is a large dodecameric enzyme with six active sites that exhibits allostery: its catalytic rate is modulated by the binding of various substrates at distal points from the active sites. A recently developed method, bond-to-bond propensity analysis, has proven capable of predicting allosteric sites in a wide range of proteins using an energy-weighted atomistic graph obtained from the protein structure and given knowledge only of the location of the active site. Bond-to-bond propensity establishes if energy fluctuations at given bonds have significant effects on any other bond in the protein, by considering their propagation through the protein graph. In this work, we use bond-to-bond propensity analysis to study different aspects of ATCase activity using three different protein structures and sources of fluctuations. First, we predict key residues and bonds involved in the transition between inactive (T) and active (R) states of ATCase by analysing allosteric substrate binding as a source of energy perturbations in the protein graph. Our computational results also indicate that the effect of multiple allosteric binding is non linear: a switching effect is observed after a particular number and arrangement of substrates is bound suggesting a form of long range communication between the distantly arranged allosteric sites. Second, cooperativity is explored by considering a bisubstrate analogue as the source of energy fluctuations at the active site, also leading to the identification of highly significant residues to the T ↔ R transition that enhance cooperativity across active sites. Finally, the inactive (T) structure is shown to exhibit a strong, non linear communication between the allosteric sites and the interface between catalytic subunits, rather than the active site. Bond-to-bond propensity thus offers an alternative route to explain allosteric and cooperative effects in terms of detailed atomistic changes to individual bonds within the protein, rather than through phenomenological, global thermodynamic arguments.
Topics: Adenosine Triphosphate; Allosteric Regulation; Allosteric Site; Aspartate Carbamoyltransferase; Aspartic Acid; Catalytic Domain; Cytidine Triphosphate; Enzyme Stability; Models, Molecular; Phosphonoacetic Acid; Protein Multimerization; Protein Subunits; Substrate Specificity
PubMed: 30038211
DOI: 10.1038/s41598-018-27992-z -
Orvosi Hetilap Mar 2019Although cytomegalovirus is one of the most prevalent viral pathogens on the globe, in immunocompetent individuals infected with cytomegalovirus usually no specific... (Review)
Review
Although cytomegalovirus is one of the most prevalent viral pathogens on the globe, in immunocompetent individuals infected with cytomegalovirus usually no specific antiviral therapy is required. In the case of impaired T-cell mediated immunity, however, latent infection can reactivate and occasionally a viral disease with organ involvement develops. The number of actually available anti-cytomegalovirus drugs is low, for prophylaxis or treatment ganciclovir, valganciclovir, foscarnet or cidofovir can be administered. The clinical use of these drugs is primarily hampered by their toxicity. In search for new treatment options, only letermovir, a terminase complex inhibitor compound showed appropriate activity and tolerability. In a placebo-controlled clinical trial on prophylactic letermovir in stem cell transplant patients, administration of the active compound resulted in a significant decrease in human cytomegalovirus reactivations as well as in prolonged survival. No toxicity affecting clinical use has been observed. For management of patients being at high risk for cytomegalovirus reactivation, appropriate antiviral strategy should be followed. Antiviral prophylaxis or diagnostics-guided pre-emptive therapy seem to be the most suitable options. Orv Hetil. 2019; 160(10): 363-369.
Topics: Acetates; Acyclovir; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Foscarnet; Ganciclovir; Humans; Immunocompromised Host; Quinazolines; Stem Cell Transplantation
PubMed: 30829057
DOI: 10.1556/650.2019.31320 -
Langmuir : the ACS Journal of Surfaces... Mar 2018The surface modification of FeO-based magnetic nanoparticles (MNPs) with N-(phosphonomethyl)iminodiacetic acid (PMIDA) was studied, and the possibility of their use as...
The surface modification of FeO-based magnetic nanoparticles (MNPs) with N-(phosphonomethyl)iminodiacetic acid (PMIDA) was studied, and the possibility of their use as magnetic resonance imaging contrast agents was shown. The effect of the added PMIDA amount, the reaction temperature and time on the degree of immobilization of this reagent on MNPs, and the hydrodynamic characteristics of their aqueous colloidal solutions have been systematically investigated for the first time. It has been shown that the optimum condition for the modification of MNPs is the reaction at 40 °C with an equimolar amount of PMIDA for 3.5 h. The modified MNPs were characterized by X-ray diffraction, transmission electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric, and CHN elemental analyses. The dependence of the hydrodynamic characteristics of the MNP colloidal solutions on the concentration and pH of the medium was studied by the dynamic light scattering method. On the basis of the obtained data, we can assume that the PMIDA molecules are fixed on the surface of the MNPs as a monomolecular layer. The modified MNPs had good colloidal stability and high magnetic properties. The calculated relaxivities r and r were 341 and 102 mmol s, respectively. The possibility of using colloidal solutions of PMIDA-modified MNPs as a T contrast agent for liver studies in vivo (at a dose of 0.6 mg kg) was demonstrated for the first time.
Topics: Animals; CHO Cells; Cell Line, Tumor; Contrast Media; Cricetulus; Humans; Liver; Magnetic Resonance Imaging; Magnetite Nanoparticles; Male; Mesocricetus; Phosphonoacetic Acid; Temperature
PubMed: 29478322
DOI: 10.1021/acs.langmuir.7b04023 -
Virology Journal Nov 2017Epstein-Barr virus (EBV) exhibits both lytic and latent (Lat. I, II, and III) phases in an infected individual. It's during the latent phase of EBV that all...
BACKGROUND
Epstein-Barr virus (EBV) exhibits both lytic and latent (Lat. I, II, and III) phases in an infected individual. It's during the latent phase of EBV that all EBV-associated cancers, including Burkitt's lymphoma, nasopharyngeal carcinoma and lymphoproliferative disease arise. Interferon-γ-inducible protein 16 (IFI16) is a well-established innate immune sensor and viral transcriptional regulator involved in response to invading DNA viruses. During latency, IFI16 remains in the nucleus, in part bound to the EBV genome; however, neither its role in EBV lytic cycle or latency has been established.
METHODS
Short interfering RNA against IFI16 and IFI16 overexpression were used to identify the role of IFI16 in the maintenance of EBV latency I. We also studied how induction of the lytic cycle affected IFI16 using the EBV positive, latently infected Akata or MUTU-1 cell lines. Akata cells were induced with TPA and MUTU-1 cells with TGF-β up to 96 h and changes in IFI16 protein were analyzed by Western blotting and immunofluorescence microscopy. To assess the mechanism of IFI16 decrease, EBV DNA replication and late lytic transcripts were blocked using the viral DNA polymerase inhibitor phosphonoacetic acid.
RESULTS
Knockdown of IFI16 mRNA by siRNA resulted in enhanced levels of EBV lytic gene expression from all temporal gene classes, as well as an increase in the total EBV genome abundance, whereas overexpression of exogenous IFI16 reversed these effects. Furthermore, 96 h after induction of the lytic cycle with either TPA (Akata) or TGF-β (MUTU-1), IFI16 protein levels decreased up to 80% as compared to the EBV-negative cell line BJAB. Reduction in IFI16 was observed in cells expressing EBV lytic envelope glycoprotein. The decreased levels of IFI16 protein do not appear to be dependent on late lytic transcripts of EBV but suggest involvement of the immediate early, early, or a combination of both gene classes.
CONCLUSIONS
Reduction of IFI16 protein levels following lytic cycle induction, as well as reactivation from latency after IFI16 mRNA knockdown suggests that IFI16 is crucial for the maintenance of EBV latency. More importantly, these results identify IFI16 as a unique host factor protein involved in the EBV lifecycle, making it a potential therapeutic target to combat EBV-related malignancies.
Topics: Burkitt Lymphoma; Cell Line, Tumor; Epstein-Barr Virus Infections; Gene Expression Regulation; Gene Knockdown Techniques; Genome, Viral; Herpesvirus 4, Human; Host-Pathogen Interactions; Humans; Nuclear Proteins; Phosphonoacetic Acid; Phosphoproteins; Tetradecanoylphorbol Acetate; Transforming Growth Factor beta; Viral Proteins; Virus Activation; Virus Latency
PubMed: 29132393
DOI: 10.1186/s12985-017-0891-5 -
Frontiers in Microbiology 2022The appearance of drug-resistant mutations in UL54 DNA polymerase and UL97 kinase genes is problematic for the treatment of human cytomegalovirus (HCMV) diseases. During...
The appearance of drug-resistant mutations in UL54 DNA polymerase and UL97 kinase genes is problematic for the treatment of human cytomegalovirus (HCMV) diseases. During treatment of HCMV infection in a pediatric hematopoietic cell transplant recipient, H600L and T700A mutations and E576G mutation were independently found in the UL54 gene. Foscarnet (FOS; phosphonoformic acid) resistance by T700A mutation is reported. Here, we investigated the role of novel mutations in drug resistance by producing recombinant viruses and a model polymerase structure. The H600L mutant virus showed an increase in resistance to ganciclovir (GCV) by 11-fold and to FOS and cidofovir (CDV) by 5-fold, compared to the wild type, while the E756G mutant virus showed an increase in resistance to FOS by 9-fold and modestly to CDV by 2-fold. With the FOS-resistant T700A mutation, only H600L produced increased FOS resistance up to 37-fold, indicating an additive effect of these mutations on FOS resistance. To gain insight into drug resistance mechanisms, a model structure for UL54 polymerase was constructed using the yeast DNA polymerase as a template. In this model, HCMV DNA polymerase contains a long palm loop domain of which H600 and T700 are located on each end and T700 interacts with the FOS binding pocket. Our results demonstrate that H600L and E756G mutations in UL54 polymerase are novel drug-resistant mutations and that the acquisition of both H600L and T700A mutations in the DNA-binding loop confers increased resistance to FOS treatment, providing novel insights for the mechanism acquiring foscarnet resistance.
PubMed: 35185843
DOI: 10.3389/fmicb.2022.771978 -
Antiviral Research Feb 2017Human cytomegalovirus UL54 DNA polymerase gene mutations that confer foscarnet resistance in clinical practice typically cluster in the amino terminal 2, palm and finger...
Human cytomegalovirus UL54 DNA polymerase gene mutations that confer foscarnet resistance in clinical practice typically cluster in the amino terminal 2, palm and finger domains. Exposure to foscarnet in cell culture selected for mutations elsewhere in UL54, including amino acid substitutions S290R in the amino terminal 1 domain and E951D in the palm 2 domain. These are newly confirmed to confer foscarnet resistance and slightly decreased ganciclovir susceptibility. Other emergent substitutions N495K, T552N and T838A are known to confer foscarnet resistance, while additional ones Q783R and V798A only slightly affected susceptibility. An expanded set of domains is involved in foscarnet resistance and its genotypic diagnosis.
Topics: Amino Acid Substitution; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; DNA-Directed DNA Polymerase; Drug Resistance, Viral; Foscarnet; Ganciclovir; Genotype; Humans; Mutation; Phenotype; Viral Proteins
PubMed: 27940027
DOI: 10.1016/j.antiviral.2016.12.003