Herpesvirus Drug Resistance Genotyping - HSV1 HSV2 HCMV VZV and HHV6

Herpedvirus drug resistance genotyping webserver, part of the herpesdrg R package, allows researchers to investigate genetic variability and viral resistance in the context of current treatments.

Below is the web tool for detecting resistance mutations in heresvirus sequencing files. Check the help page for further details.

Upload a file to return resistance data




Clinical Overview - mutations > 10% frequency




Identified Resistant mutants



Graphics showing location of identified resistance mutations, in context to all database mutations


Gene - drug resistance heatmap, showing number of entries for each combination


This page desciribes usage and results from the Resistance Genotyping homepage

Inputs
Currently this method only supports analysis of a single sequence / variant file at a time The universal upload file box should be used to upload any of the accepted file formats. Currently:
  • Fasta (Whole genome, or fragments i.e. UL54 & UL89
  • Varaint Call Format >= Ver4.0
  • Varscan tabluated format

Options
Once uploaded the genetic information is annotated & resistant variants identified. Default behaviour is to Include only resistance data in database that is from in vitro studies. Users can include data from anecdotal sources e.g. Mutations noted as potentially resistant from a drug trial. By clicking the checkbox 'Include anecdotal data'

Clinical Overview
A concise summary of the processed resistance phenotype against the therepeutic options in the database. Cutoff values are in line with the recommendations from 'The Third International Consensus Guidelines on the Managemenet of Cytomegalovirus in Solid-Organ Transplantation' and are presented as follows:
  • High level (any mutation confers a fold change above 15)
  • Moderate level (maximal fold change returned is between 5-15)
  • Low resistance (maximal fold change returned is between 2-5)
  • No Resistance (maximal fold change returned was less than 2, or only anecdotal 'Polymorphism' was returned)
  • Resistant, magnitude unknown ( only anecdotal resistant data was returned)
  • NA (no mutations returned)


Comprehensive resistance
Shows all records in the resistance database identified in the uploaded sample.
green: Genetic information. Gene - Amino acid change realationship. freq: percentage of variant_reads / (all reads), data shown in the ref_var_count column. ref_pos: relative nucleotide position in merlin strain.

red: Resistant Phenotype. Headers are drugs recorded within the database. Rows are entries , where a mutation can map to many entries & an entry can map to many drugs. Values are the EC50 fold change determined relative to a wild type virus. 'Resistant' or 'Polymorphism' in entries are typically associated with anecdotal or less defined entries & users should consult the references

blue: Reference information. Hyperlinks to the original reference where available. test_method is a brief summary of the method used to derive the entry as descriped in the journal scraped, test_method_class in even more brief.

co_gene and co_aa: some database entries contain tested viruses with co-occuring marker transferred mutations. Where flagged these columns are filled.


Disclaimer
This database has been created and is maintained by the Breuer Lab at UCL as a benefit to the research and education community. This tool is provided on an 'as is, best endeavours' basis only, and without guarantee to its accuracy or reliability.
We clearly state here that the tool is not validated for use in a diagnostic or clinical or care context
We clearly state here that any file uploaded should be devoid of patient identifiable features, such as filename.
When you upload a file to use this web service, you are accepting these terms.

Privacy Policy

Every time you access the hosted 'Herpesvirus Drug Resistance Genotyping' hosted UCL web address we reserve the right to register the following data for statistical and troubleshooting purposes.

  • Date and time of access
  • City of IP adress. File contents are untouched.




last updated: 07/05/2020


Cytomegalovirus

The prevention and treatment of Herpesviruses is essential in management of solid organ transplant (SOT), hematopoietic stem cell transplant (HSCT) and other immunocompromised hosts. Althought primary infections tend to be asymntomatic within healthy individuals, it is a major cause of morbidity and chronic ill-health to congenitally infected babies & those mentioned. Although a handful of treatment options are available such as Ganciclovir, Aciclovir and Foscarnet, emergence of resistance is now found for all current drugs and pose a significant threat due to aggressive disease course and a greater mortality risk. Early detection of resistance is important to inform alternative treatments.


Data

The database underpinning herpesdrg contains the link between gene, aachange & EC50 fold change to wild type virus developed by the Breuer lab at UCL & GOSH. To capture new resistant mutations, articles in peer-reviewed journals are searched monthly using a PubMed search with key terms. Regular expressions narrow down the list to those including mutations. To minimise any subjectivity, where relevant we capture many data points per mutation which are included in reporting methods here. If you spot mistakes or omissions in the database either contact oscar.charles.18@ucl.ac.uk or alter the github /inst/db files.


Method:
Results generated are relative to the well characterised reference strain Merlin. When loading a fasta file, 'MAFFT --add --keeplength' is used to create an alignment to this reference. Therefore, whole genome sequences as well as fasta files containing genetic fragments are accepted.. Alignments are converted to VCF format using snp-sites. Custom R functions then call resistance from the database.

Open Source

The database, functions and application are available as an R package in Github here.



Ackowledgements

We would like to thank the MRC and Wellcome Trust as sponsors of the Breuer lab, for enabling this work. The Breuer Lab work in close co-operation with the Pathogen Genomics Unit