scholarly journals Antiviral Drug Resistance of Human Cytomegalovirus

2010 ◽  
Vol 23 (4) ◽  
pp. 689-712 ◽  
Author(s):  
Nell S. Lurain ◽  
Sunwen Chou
Keyword(s):  
Drug Resistance ◽  
Dna Polymerase ◽  
Human Cytomegalovirus ◽  
Treatment Options ◽  
Antiviral Drug ◽  
Resistance Mutations ◽  
Phenotypic Analysis ◽  
Antiviral Drug Resistance ◽  
Phenotypic Methods ◽  
Approved Drugs

SUMMARY The study of human cytomegalovirus (HCMV) antiviral drug resistance has enhanced knowledge of the virological targets and the mechanisms of antiviral activity. The currently approved drugs, ganciclovir (GCV), foscarnet (FOS), and cidofovir (CDV), target the viral DNA polymerase. GCV anabolism also requires phosphorylation by the virus-encoded UL97 kinase. GCV resistance mutations have been identified in both genes, while FOS and CDV mutations occur only in the DNA polymerase gene. Confirmation of resistance mutations requires phenotypic analysis; however, phenotypic assays are too time-consuming for diagnostic purposes. Genotypic assays based on sequencing provide more rapid results but are dependent on prior validation by phenotypic methods. Reports from many laboratories have produced an evolving list of confirmed resistance mutations, although differences in interpretation have led to some confusion. Recombinant phenotyping methods performed in a few research laboratories have resolved some of the conflicting results. Treatment options for drug-resistant HCMV infections are complex and have not been subjected to controlled clinical trials, although consensus guidelines have been proposed. This review summarizes the virological and clinical data pertaining to HCMV antiviral drug resistance.

scholarly journals Interstrain Variation in the Human Cytomegalovirus DNA Polymerase Sequence and Its Effect on Genotypic Diagnosis of Antiviral Drug Resistance

1999 ◽  
Vol 43 (6) ◽  
pp. 1500-1502 ◽  
Author(s):  
Sunwen Chou ◽  
Nell S. Lurain ◽  
Adriana Weinberg ◽  
Guang-Yung Cai ◽  
Prem L. Sharma ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Amino Acid ◽  
Dna Polymerase ◽  
Human Cytomegalovirus ◽  
Antiviral Drug ◽  
Resistance Mutations ◽  
Sequence Alignments ◽  
Coding Sequence ◽  
Antiviral Drug Resistance ◽  
Almost All

ABSTRACT The polymerase (pol) coding sequence was determined for 40 independent clinical cytomegalovirus isolates sensitive to ganciclovir and foscarnet. Sequence alignments showed >98% interstrain homology and amino acid variation in only 4% of the 1,237 codons. Almost all variation occurred outside of conserved functional domains where resistance mutations have been identified.

scholarly journals Performance of NS3, NS5a AND NS5b Hepatitis C Virus (HCV) Antiviral Resistance Sequencing Assays

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S40-S40
Author(s):  
Jamie Nutt ◽  
James Grantham ◽  
Marilyn Smith ◽  
Emily Smith ◽  
Ashley Wedin ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Sanger Sequencing ◽  
Hot Spot ◽  
Treatment Options ◽  
Antiviral Drug ◽  
Resistance Testing ◽  
Clinical Samples ◽  
Resistance Mutations ◽  
Hcv Genotype ◽  
Antiviral Drug Resistance

Abstract Background HCV genotype 1a (HCV g1a) followed by HCV g1b, –g2, and –g3 are the most common etiologic agents in the ~3 million current HCV-infections in the US. To achieve effective therapy, antiviral drug resistance testing is often essential but not fully available. Knowledge of both the genotype and the presence of HCV mutations in the genes of the major drug targets (NS3, NS5A and NS5B) can assist in optimal treatment selection. Methods The HCV genotype of 1000 HCV positive clinical plasmas and sera was determined (HCVg Direct, GenMark). Ten independent Sanger sequencing assays detecting antiviral drug resistance mutations in the genes encoding NS3, NS5a, and NS5b were developed. Six of these assays address mutations in all three genes in the two most common genotypes (HCV g1a and g1b). In addition, four more assays address mutations in NS5a and NS5b of HCV g2 and g3. These mutations are resistance determinants against 11 anti-HCV drugs as shown in Figure 1. A streamlined workflow employs conventional reverse transcriptase PCR, gel electrophoresis, spectrophotometry, bi-directional Sanger sequencing and reporting. The assays were designed to cover hot spot regions and capturing all known resistance mutations in NS3, NS5a and NS5b. Results Consistent with previous US HCV incidence reports, g1a, g1b, g2, and g3 comprised 99% of 1000 sequentially tested HCV patient specimens (62%, 12%, 11%, and 14%, respectively). Testing of more than 20 clinical samples each for g1a, g1b, g2, and g3 resulted in successful detection of NS3, NS5a, and NS5b mutations that confer drug resistance. The design successfully permitted detection of relevant mutations known to date for all 11 drugs. The number of reportable mutations range from 20 ‒ 36, 9 ‒ 49, and 10 ‒ 29 for the NS3, NS5a, and NS5b inhibitors, respectively (Figure 1). Conclusion These assays provide the most comprehensive commercially available antiviral drug resistance information to date for mutations in HCV NS3, NS5A, and NS5B. This testing will assist physicians in deciding on the most appropriate treatment options for their patients. Disclosures J. Nutt, Viracor Eurofins Laboratories: Employee, Salary; 
J. Grantham, Viracor Eurofins Laboratories: Employee, Salary; M. Smith, Viracor Eurofins Laboratories: Employee, Salary; E. Smith, Viracor Eurofins Laboratories: Employee, Salary; A. Wedin, Viracor Eurofins Laboratories: Employee, Salary; 
A. Tyler, Viracor Eurofins Laboratories: Employee, Salary; M. Miralles, Viracor Eurofins Laboratories: Employee, Salary; S. Kleiboeker, Viracor Eurofins Laboratories: Employee, Salary; M. Wissel, Viracor Eurofins Laboratories: Employee, Salary

scholarly journals Differentiation between Polymorphisms and Resistance-Associated Mutations in Human Cytomegalovirus DNA Polymerase

2010 ◽  
Vol 54 (12) ◽  
pp. 5004-5011 ◽  
Author(s):  
Meike Chevillotte ◽  
Ina Ersing ◽  
Thomas Mertens ◽  
Jens von Einem
Keyword(s):  
Drug Resistance ◽  
Dna Polymerase ◽  
Human Cytomegalovirus ◽  
Antiviral Drug ◽  
Drug Susceptibility ◽  
Resistance Testing ◽  
Resistance Mutations ◽  
Genotypic Resistance ◽  
Drug Resistance Testing ◽  
Genotypic Resistance Testing

ABSTRACT Specific mutations in the human cytomegalovirus (HCMV) DNA polymerase (pUL54) are known to confer resistance against all currently licensed drugs for treatment of HCMV infection and disease. Following the widespread use of antivirals, the occurrence of HCMV drug resistance is constantly increasing. Recently, diagnostic laboratories have started to replace phenotypic drug resistance testing with genotypic resistance testing. However, the reliability and success of genotypic testing highly depend on the availability of high-quality phenotypic resistance data for each individual mutation and for combinations of mutations, with the latter being increasingly found in patients' HCMV isolates. We performed clonal marker transfer experiments to investigate the impacts of 7 different UL54 point mutations and also of combinations of these mutations on drug susceptibility and viral replicative fitness. We show that several mutations—S695T, A972V, K415R, S291P, and A692V—of suspected but uncertain drug susceptibility phenotype, either alone or in combination, were not relevant to antiviral drug resistance. In contrast, the combination of two mutations individually characterized previously—E756K and D413E—conferred high-grade loss of susceptibility to all three antivirals. Our results have been added to the newly available database of all published HCMV resistance mutations (http://www.informatik.uni-ulm.de/ni/mitarbeiter/HKestler/hcmv/index.html ). These data will allow better interpretation of genotypic data and further improve the basis for drug resistance testing.

A Mass Spectrometry-based Method to Detect Antiviral Drug Resistance in Human Cytomegalovirus

2009 ◽  
Vol 82 (2) ◽  
pp. A51
Author(s):  
Clara Posthuma ◽  
Martha Van der Beek ◽  
Caroline Van der Blij ◽  
Willy Spaan ◽  
Louis Kroes ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Drug Resistance ◽  
Human Cytomegalovirus ◽  
Antiviral Drug ◽  
Antiviral Drug Resistance

Computational Coevolution of Antiviral Drug Resistance

1998 ◽  
Vol 4 (1) ◽  
pp. 41-59 ◽  
Author(s):  
Christopher D. Rosin ◽  
Richard K. Belew ◽  
Garrett M. Morris ◽  
Arthur J. Olson ◽  
David S. Goodsell
Keyword(s):  
Drug Resistance ◽  
Broad Class ◽  
Antiviral Drug ◽  
Resistant Mutant ◽  
Approximate Model ◽  
Cross Resistance ◽  
Resistance Mutations ◽  
Wide Range ◽  
Antiviral Drug Resistance ◽  
Mutant Forms

An understanding of antiviral drug resistance is important in the design of effective drugs. Comprehensive features of the interaction between drug designs and resistance mutations are difficult to study experimentally because of the very large numbers of drugs and mutants involved. We describe a computational framework for studying antiviral drug resistance. Data on HIV-1 protease are used to derive an approximate model that predicts interaction of a wide range of mutant forms of the protease with a broad class of protease inhibitors. An algorithm based on competitive coevolution is used to find highly resistant mutant forms of the protease, and effective inhibitors against such mutants, in the context of the model. We use this method to characterize general features of inhibitors that are effective in overcoming resistance, and to study related issues of selection pathways, cross-resistance, and combination therapies.

scholarly journals cmvdrg - An R package for Human Cytomegalovirus antiviral Drug Resistance Genotyping

2020 ◽  
Author(s):  
Oscar J Charles ◽  
Cristina Venturini ◽  
Judith Breuer
Keyword(s):  
Drug Resistance ◽  
Open Source ◽  
Human Cytomegalovirus ◽  
Antiviral Drug ◽  
R Package ◽  
Effective Vaccine ◽  
Analysis Tool ◽  
Resistance Mutations ◽  
Drug Resistance Genotyping ◽  
User Friendly

AbstractThe prevention and treatment of HCMV infection is based on the utilization of antiviral therapies as HCMV lacks an effective vaccine. The rise of drug resistance is therefore an increasing patient threat. We identified the need for an open source and comprehensive HCMV resistance mutations database, to support the research community in this area. Here we present “Cytomegalovirus Drug Resistance Genotyping” (cmvdrg), a freely available database contained within an easily accessible R package, which provides a succinct extraction of literature material in the form of a text file database. Additionally, cmvdrg includes methods for calling resistance in common sequencing files and an optional user-friendly web interface.AvailabilityThe cmvdrg package is freely available under the GNU GPL v3 license at https://github.com/ucl-pathgenomics/cmvdrg,One Sentence SummaryCurrently data regarding Human Cytomegalovirus resistant mutations are contained in unconnected literature sources, here we present an exhaustive open source database and analysis tool for the community.

scholarly journals Cytomegalovirus Replication Steps and the Actions of Antiviral Drugs

2018 ◽  
Vol 16 (2) ◽  
pp. 80-95 ◽  
Author(s):  
Ashwaq Ahmed Abdullah ◽  
Krishnan Nair Balakrishnan ◽  
Jamilu Abubakar Bala ◽  
Faez Firdaus Jesse Abdullah ◽  
Zeenatul Allaudin Nazariah ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Virus Replication ◽  
Human Cytomegalovirus ◽  
Adverse Reactions ◽  
Antiviral Drug ◽  
Antiviral Drugs ◽  
Active Infection ◽  
Detailed Understanding ◽  
Cellular Factors ◽  
Antiviral Drug Resistance

Human cytomegalovirus (HCMV) is a beta herpesvirus that inflicts an active infection in the fetus and immunosuppressive patients. The virus encodes many proteins that work together with cellular factors to achieve virus replication. In addition to vaccines, antiviral drugs can be deployed to manipulate how the virus replicates and minimize its pathogenicity. The five antiviral drugs approved by the Food and Drug Administration (FDA) have shown adverse reactions and the antiviral drug resistance were reported. Hence, this warrants the need for urgent development of a novel antiviral drug. Detailed understanding of the virus replication steps and how cellular signals interact with these steps will be key for pharmacological developments of for anti HCMV drugs. This review summarized all the drugs that target the virus proteins and cell signals that mediate CMV replication.

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