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Current Opinion in Infectious Diseases Dec 2022This review summarizes the literature on acyclovir resistant herpes infections and the most recent data pertinent to diagnosis and treatment in the immunocompromised... (Review)
Review
PURPOSE OF REVIEW
This review summarizes the literature on acyclovir resistant herpes infections and the most recent data pertinent to diagnosis and treatment in the immunocompromised patient population.
RECENT FINDINGS
Although fairly rare, acyclovir resistant herpes infections can be challenging to diagnose. Clinicians should be aware of this entity when facing refractory herpes infections. With updated diagnostics, the diagnosis is usually made through viral culture and sequencing. Therapeutic choices depend on the extent of disease. Topical therapy may be appropriate for mucocutaneous disease. Intravenous antiviral therapies such as foscarnet and cidofovir may be necessary for disseminated, ophthalmologic, central nervous system, or visceral disease. Experimental therapies such as pritelivir are in clinical trials.
SUMMARY
Immunosuppressed patients are at risk for developing acyclovir-resistant herpes, which can be challenging to diagnose and treat, although emerging therapeutic options look promising.
Topics: Humans; Organophosphonates; Cytosine; Acyclovir; Foscarnet; Antiviral Agents; Herpes Simplex; Herpesviridae Infections
PubMed: 36206151
DOI: 10.1097/QCO.0000000000000889 -
Molecules (Basel, Switzerland) Sep 2022The chemical reactivity of 3-[()-3-(dimethylamino)-2-propenoyl]-4-hydroxy-1-methy-2(1)-quinolinone () towards some phosphorus reagents was studied. The enaminone was...
The chemical reactivity of 3-[()-3-(dimethylamino)-2-propenoyl]-4-hydroxy-1-methy-2(1)-quinolinone () towards some phosphorus reagents was studied. The enaminone was cyclized into pyranoquinolinylphosphonate via treatment with diethyl phosphite in basic medium. However, its reaction with triethoxy phosphonoacetate gave the substituted oxopyranylphosphonate . Using the same reaction conditions, both thioxopyridinylphosphonate and oxopyranylphosphonate were produced via a reaction of enaminone with both diethyl 2-amino-2-thioxoethylphosphonate and diethyl vinylphosphonate, respectively, in low yields. In addition, the two novel oxopyridinylphosphonates and were obtained by treatment of enaminone with a diethyl cyanomethylphosphonate reagent. Two oaxathiaphosphininyl derivatives, and were obtained by treatment of the enaminone with -diethyl dithiophosphoric acid under different reaction conditions. Diazaphosphininyl and oxazaphosphininyl derivatives were obtained in excellent yields using a -phenylphosphonic diamide reagent under different reaction conditions. The treatment of the enaminone with phosphorus pentasulfide produced the non-phosphorylated product thioxothiopyranoquinolinone . Finally, the enaminone was turned into oxathiaphosphininyl using Lawesson's reagent. The possible reaction mechanisms of the formation of these products were discussed. The structures of newly isolated products were established by elemental analysis and spectral tools. The compounds were evaluated for their antioxidant activities.
Topics: Antioxidants; Diamide; Indicators and Reagents; Organophosphonates; Phosphites; Phosphonoacetic Acid; Phosphorus; Quinolones
PubMed: 36144697
DOI: 10.3390/molecules27185960 -
Inorganic Chemistry Oct 2022Carbon and phosphorous are two primary elements common to the bio-geosphere and are omnipresent in both biotic and abiotic arenas. Phosphonate and carboxylate are...
Carbon and phosphorous are two primary elements common to the bio-geosphere and are omnipresent in both biotic and abiotic arenas. Phosphonate and carboxylate are considered as building blocks of glyphosate and humic substances and constituents of the cellular wall of bacteria and are the driving functionalities for most of the chemical interactions involving these two elements. Phosphonocarboxylates, a combination of both the functionalities in one moiety, are ideal models to dig deep into for understanding the chemical interactions of the two functional groups with metal ions. Phosphorous and carbon majorly exist as inorganic/organic phosphate and carboxylate, respectively, in the bio-geosphere. Aquatic contamination is a major concern for uranium, and the presence of complexing agents would alter the uranium concentrations in aquifers. Determination of solution thermodynamic parameters, speciation plots, redox patterns, -pH diagrams, coordination structures, and molecular-level understanding by density functional theory calculations was carried out to interpret the uranyl (UO) interaction with three environmentally relevant phosphonocarboxylates, namely, phosphono-formic acid (PFA), phosphono-acetic acid (PAA), and phosphono-propanoic acid (PPA). UO forms 1:1 complexes with the three phosphonocarboxylates in the monoprotonated form, having nearly the same stability, and the complexes [UO(PFAH)], [UO(PAAH)], and [UO(PPAH)] involve chelate formation of five, six, and seven membered rings, respectively, through the participation of an oxygen each from the carboxylate and phosphonate, strengthened by an intra-molecular hydrogen bonding through the proton of the phosphonate moiety with uranyl oxygen. The complex formations are favored both enthalpically and entropically, with the latter being more contributive to the overall free energy of formation. The redox speciation showed an aqueous soluble complex formation over a wide pH range of 1-8. Electrospray ionization mass spectrometry and extended X-ray absorption fine structure established the coordination modes, which are further corroborated by density functional calculations. The knowledge gained from the present studies provide potential inputs in framing the cleanup, sequestering, microbial, and bio-remediation strategies for uranyl from aquatic environments.
Topics: Carbon; Carboxylic Acids; Humic Substances; Ions; Organophosphates; Organophosphonates; Oxidation-Reduction; Oxygen; Protons; Uranium
PubMed: 36123167
DOI: 10.1021/acs.inorgchem.2c01991 -
The Journal of Antimicrobial... Oct 2022Prolonged antiviral therapy in immunocompromised individuals can result in the emergence of (multi)drug-resistant herpes simplex virus 1 (HSV-1) infections, forming a...
BACKGROUND
Prolonged antiviral therapy in immunocompromised individuals can result in the emergence of (multi)drug-resistant herpes simplex virus 1 (HSV-1) infections, forming a therapeutic challenge.
OBJECTIVES
To evaluate spatial and temporal differences in drug resistance of HSV-1 samples from a HSCT recipient and to determine the effect of resistance mutations on viral replication fitness.
PATIENTS AND METHODS
Five HSV-1 isolates were recovered from a HSCT recipient who suffered from persistent HSV-1 lesions, consecutively treated with aciclovir, foscarnet, cidofovir and a combination of ganciclovir and cidofovir. Spatial and temporal differences in HSV-1 drug resistance were evaluated genotypically [Sanger sequencing and next-generation sequencing (NGS) of the viral thymidine kinase (TK) and DNA polymerase (DP)] and phenotypically (plaque reduction assay). Viral replication fitness was determined by dual infection competition assays.
RESULTS
Rapid evolution to aciclovir and foscarnet resistance was observed due to acquisition of TK (A189V and R222H) and DP (L778M and L802F) mutations. Virus isolates showed heterogeneous populations, spatial virus compartmentalization and minor viral variants in three out of five isolates (detectable by NGS but not by Sanger sequencing). Mutations in the TK and DP genes did not alter replication fitness without drug pressure. TK and/or DP mutants influenced replication fitness under antiviral pressure and showed increased fitness under pressure of the drug they showed resistance to.
CONCLUSIONS
The use of NGS and dual infection competition assays revealed rapid evolution of HSV-1 drug resistance in a HSCT recipient with spatial and temporal compartmentalization of viral variants that had altered replication fitness under antiviral pressure.
Topics: Humans; Herpesvirus 1, Human; Thymidine Kinase; Foscarnet; Cidofovir; Herpes Simplex; Drug Resistance, Viral; Acyclovir; DNA-Directed DNA Polymerase; Antiviral Agents; Mutation; Virus Replication
PubMed: 36059135
DOI: 10.1093/jac/dkac297 -
Journal of Medical Virology Dec 2022HSV-2 antiviral resistance mainly occurs in immunocompromised patients and especially in HIV-positive individuals receiving long-term antiviral treatment. Those...
HSV-2 antiviral resistance mainly occurs in immunocompromised patients and especially in HIV-positive individuals receiving long-term antiviral treatment. Those situations can be challenging as few alternatives are available for HSV infection management. To describe clinical and virological significance of two novel potential HSV-2 resistance mutations after treating an obese patient with a pseudotumoral genital HSV-related lesion. Consecutive different antiviral treatments were used: valacyclovir (VACV) then foscarnet (FOS) then topical cidofovir (CDV) and finally imiquimod. Under VACV, genotypic resistance testing revealed a novel mutation within viral thymidine kinase (TK, gene UL23) not previously reported but probably accounting for antiviral resistance: W89G, similar to W88R mutation reported in HSV-1 TK, known to be associated with ACV resistance for HSV-1. Under FOS, while initial mutations were still present, a second genotypic resistance testing performed on persisting lesions showed a novel mutation within viral DNA polymerase (DNA pol, gene UL30): C625R. All three antivirals used in this case are small molecules and pharmacokinetics of VACV, FOS, and CDV have not been evaluated in animals and there are very few studies in human. As small molecules are poorly bound to proteins and distribution volume is increased in obese patients, there is risk of underdosage. This mechanism is suspected to be involved in emergence of resistance mutation and further data is needed to adapt, closely to patient profile, antiviral dosage. This report describes a chronic HSV-2 genital lesion, with resistance to current antivirals and novel mutations within viral TK and DNA pol which may confer antiviral resistance.
Topics: Acyclovir; Antiviral Agents; Cidofovir; DNA-Directed DNA Polymerase; Drug Resistance, Viral; Foscarnet; Genitalia; Herpes Simplex; Herpesvirus 2, Human; Humans; Imiquimod; Mutation; Obesity; Thymidine Kinase; Valacyclovir
PubMed: 35973907
DOI: 10.1002/jmv.28070 -
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 -
Journal of Nanobiotechnology Jul 2022Cytomegalovirus (CMV) pneumonia is a major cause of morbidity and mortality in immunodeficiency individuals, including transplant recipients and Acquired Immune...
BACKGROUND
Cytomegalovirus (CMV) pneumonia is a major cause of morbidity and mortality in immunodeficiency individuals, including transplant recipients and Acquired Immune Deficiency Syndrome patients. Antiviral drugs ganciclovir (GCV) and phosphonoformate (PFA) are first-line agents for pneumonia caused by herpesvirus infection. However, the therapy suffers from various limitations such as low efficiency, drug resistance, toxicity, and lack of specificity.
METHODS
The antiviral drugs GCV and PFA were loaded into the pH-responsive nanoparticles fabricated by poly(lactic-co-glycolic acid) (PLGA) and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and further coated with cell membranes derived from bone marrow mesenchymal stem cells to form artificial stem cells, namely MPDGP. We evaluated the viral suppression effects of MPDGP in vitro and in vivo.
RESULTS
MPDGP showed significant inflammation tropism and efficient suppression of viral replication and virus infection-associated inflammation in the CMV-induced pneumonia model. The synergistic effects of the combination of viral DNA elongation inhibitor GCV and viral DNA polymerase inhibitor PFA on suppressing the inflammation efficiently.
CONCLUSION
The present study develops a novel therapeutic intervention using artificial stem cells to deliver antiviral drugs at inflammatory sites, which shows great potential for the targeted treatment of pneumonia. To our best knowledge, we are the first to fabricate this kind of artificial stem cell to deliver antiviral drugs for pneumonia treatment.
Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Fatty Acids, Monounsaturated; Foscarnet; Ganciclovir; Humans; Inflammation; Nanoparticle Drug Delivery System; Pneumonia; Polylactic Acid-Polyglycolic Acid Copolymer; Quaternary Ammonium Compounds; Stem Cells
PubMed: 35842662
DOI: 10.1186/s12951-022-01547-x -
Transplantation Proceedings 2022Cytomegalovirus (CMV) is considered one of the most notable pathogens that affect patients after solid organ transplantation (SOT), especially small bowel transplant...
Cytomegalovirus (CMV) is considered one of the most notable pathogens that affect patients after solid organ transplantation (SOT), especially small bowel transplant patients with a risk of high mortality rate. Its management relies historically on the use of CMV DNA polymerase inhibitors (namely, ganciclovir and valganciclovir). Second-line options include foscarnet and cidofovir, which are highly nephrotoxic and thus less preferred and only used in ganciclovir intolerance or resistance cases. Letermovir is a novel antiviral agent approved for CMV prophylaxis in hematopoietic stem cell transplant, but not for SOT (neither for prophylaxis nor for treatment). We report the first case on the successful use of letermovir in treating CMV disease in a small bowel transplant patient who failed to achieve viral clearance due to ganciclovir resistance and severe intolerance to foscarnet.
Topics: Acetates; Antiviral Agents; Cidofovir; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Foscarnet; Ganciclovir; Humans; Nucleic Acid Synthesis Inhibitors; Quinazolines; Transplant Recipients; Valganciclovir
PubMed: 35842318
DOI: 10.1016/j.transproceed.2022.04.021 -
Journal of Infection and Chemotherapy :... Oct 2022Cytomegalovirus (CMV) is a major infectious agent causing severe complications in allogeneic hematopoietic cell transplantation (HCT) recipients, thereby warranting the...
Cytomegalovirus (CMV) is a major infectious agent causing severe complications in allogeneic hematopoietic cell transplantation (HCT) recipients, thereby warranting the need for aggressive preemptive or targeted antiviral therapy. However, prolonged or repeated use of antiviral agents, such as ganciclovir (GCV), foscarnet (FOS), and cidofovir (CDV), can result in drug-resistant CMV infection, posing challenges to successful outcomes. Here, we report a case of a patient with acute myeloid leukemia and drug-resistant CMV infection who presented with persistent CMV DNAemia, colitis, pneumonia, and encephalitis. An intra-host diversity of UL97 and UL54 mutations were detected through the genotypic resistance testing conducted on two blood samples (D+199 and D+224) and a cerebrospinal fluid (CSF) specimen (D+260) collected from the patient. UL97 L595W/L595F and L595W mutations were detected in the blood and CSF samples, respectively, that conferred GCV resistance. UL54 F412L mutation detected in all three samples conferred GCV/CDV resistance. However, the V787L mutation of UL54, conferring GCV/FOS resistance, was observed only in the D+224 blood sample. Despite combination therapy with FOS and high dose GCV and adjunctive therapy with leflunomide, the patient died from CMV infection and multiple organ failure on D+279. Further data on resistant mutations and intra-host diversity of CMV should be accumulated to elucidate the antiviral resistance and related outcomes.
Topics: Antiviral Agents; Cidofovir; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Foscarnet; Ganciclovir; Hematopoietic Stem Cell Transplantation; Humans; Mutation; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 35810104
DOI: 10.1016/j.jiac.2022.05.020 -
Journal of Virology Jul 2022Pseudorabies virus (PRV) is a porcine alphaherpesvirus that belongs to the family. We showed earlier that infection of porcine epithelial cells with PRV triggers...
Pseudorabies virus (PRV) is a porcine alphaherpesvirus that belongs to the family. We showed earlier that infection of porcine epithelial cells with PRV triggers activation of the nuclear factor κB (NF-κB) pathway, a pivotal signaling axis in the early immune response. However, PRV-induced NF-κB activation does not lead to NF-κB-dependent gene expression. Here, using electrophoretic mobility shift assays (EMSAs), we show that PRV does not disrupt the ability of NF-κB to interact with its κB target sites. Assessing basal cellular transcriptional activity in PRV-infected cells by quantitation of prespliced transcripts of constitutively expressed genes uncovered a broad suppression of cellular transcription by PRV, which also affects the inducible expression of NF-κB target genes. Host cell transcription inhibition was rescued when viral genome replication was blocked using phosphonoacetic acid (PAA). Remarkably, we found that host gene expression shutoff in PRV-infected cells correlated with a substantial retention of the NF-κB subunit p65, the TATA box binding protein, and RNA polymerase II-essential factors required for (NF-κB-dependent) gene transcription-in expanding PRV replication centers in the nucleus and thereby away from the host chromatin. This study reveals a potent mechanism used by the alphaherpesvirus PRV to steer the protein production capacity of infected cells to viral proteins by preventing expression of host genes, including inducible genes involved in mounting antiviral responses. Herpesviruses are highly successful pathogens that cause lifelong persistent infections of their host. Modulation of the intracellular environment of infected cells is imperative for the success of virus infections. We reported earlier that a DNA damage response in epithelial cells infected with the alphaherpesvirus pseudorabies virus (PRV) results in activation of the hallmark proinflammatory NF-κB signaling axis but, remarkably, that this activation does not lead to NF-κB-induced (proinflammatory) gene expression. Here, we report that PRV-mediated inhibition of host gene expression stretches beyond NF-κB-dependent gene expression and in fact reflects a broad inhibition of host gene transcription, which correlates with a substantial recruitment of essential host transcription factors in viral replication compartments in the nucleus, away from the host chromatin. These data uncover a potent alphaherpesvirus mechanism to interfere with production of host proteins, including proteins involved in antiviral responses.
Topics: Animals; Herpesvirus 1, Suid; Host Microbial Interactions; NF-kappa B; Pseudorabies; Swine; Swine Diseases; Transcription, Genetic
PubMed: 35730976
DOI: 10.1128/jvi.00714-22