Online services

From Hivdrc

Contents 1 Background 2 HIV Protease Susceptibility Prediction Service 3 HIV RT Susceptibility Prediction Service 4 User Guide 4.1 Using the service 4.2 The result pages 4.3 Programmatic access via Web services 4.4 Invoke service from Bioclipse

Background

The HIV protease and reverse transcriptase (RT) are two major drug targets in HIV therapy. HIV is capable to escape current antiviral therapy directed at these targets by evolving into drug-resistant variants with more or less complex mutation patterns. HIVDRC partners have implemented two services that predict drug susceptibility for protease inhibitors (PIs) and nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) from the mutation patterns of different HIV strains' genome sequences. These services may thus permit the selection of optimal treatment for individual patients based on the mutations patterns of the patient's particular HIV strain.

If you use any of these services, please cite:

O. Spjuth, M. Eklund, M. Lapins,M. Junaid, JE. Wikberg
Services for prediction of drug susceptibility for HIV proteases and reverse  transcriptases at the HIV Drug Research Centre.
Bioinformatics. 2011 Apr 14. Epub ahead of print

HIV Protease Susceptibility Prediction Service

This service is based on the proteochemometric model described in Lapins et al., BMC Bioinformatics (2008) 9:181, and allows for prediction of drug susceptibility of seven clinically used PIs from the HIV protease sequence. The model is based on 828 mutated HIV protease genome sequences and the experimental susceptibility data for the seven protease inhibitors measured by their ability to inhibit the replications of the respective mutated HIV variant in vitro; in total the model is based on 4794 protease sequence-inhibitor combinations. For more information, please see:

M. Lapins, M. Eklund, O. Spjuth, P. Prusis, and J.E.S. Wikberg.
Proteochemometric modeling of HIV protease susceptibility
BMC Bioinformatics (2008), 9:181, doi:10.1186/1471-2105-9-181

Please cite this paper if you use the service in scientific research. Access the service here.

HIV RT Susceptibility Prediction Service

This service is based on a proteochemometric model which is submitted for publication, and allows for prediction of drug susceptibility of eight NRTIs (of which seven are in current clinical use) from the HIV protease sequence. The model is based on 728 mutated HIV reverse transcriptase genome sequences and the experimental susceptibility data for the eight NRTIs measured by their ability to inhibit the replications of the respective mutated HIV variant in vitro; in total the model is based on 4495 reverse transcriptase sequence-inhibitor combinations. For more information, please see:

Junaid M,  Lapins M,  Eklund M,  Spjuth O,  Wikberg JES, 2010
Proteochemometric Modeling of the Susceptibility of Mutated Variants of the HIV-1 Virus to Reverse Transcriptase Inhibitors.
PLoS ONE 5(12): e14353. doi:10.1371/journal.pone.0014353

Please cite this paper if you use the service in scientific research. Access the service here.

User Guide

Using the service

The protease and the reverse transcriptase services are equipped with similar user interfaces. To use the services you have three options for inputing, respectively, the HIV protease or reverse transcriptase sequences:

1. Input a comma-separated list of mutations.
2. Select one or more mutations from the pulldown lists
3. Paste a complete sequence into the designated textbox*.

• (Note that for the reverse transcriptase only the 240 N-terminal amino acids are used (i.e. the enzymes active site) as recorded in the Stanford HIV database; see: Soo-Yon Rhee, Matthew J, Gonzales, Rami Kantor, Bradley J, at al. (2003) Human immunodeficiency virus reverse transcriptase and protease sequence database. Nucleic Acids Research 31: 298-303)

After you have done any of the above, click the Analyze button to start the prediction service. The selected mutations will appear above the Analyze button, showing your complete selection of mutations (see figure below).

Example usage of the HIV Protease service. The user has inputted a free text mutation in the topmost inputbox (62L) and also selected a mutation in one of the pulldown boxes (10V). This is showed above the Analyze button.

The result pages

The result page of a service invocation can be seen in the figure below:

Results of the HIV Protease service. To the left is displayed a chart with the predicted susceptibility values. To the right is a table of the clinical cutoff values. More details are also available on the page.

If a patient's virus is less susceptible to a particular drug, that drug is less likely to work for him or her. Even if a patient shows reduced susceptibility to a particular drug, that drug may still be effective, as long the reduction of susceptibility is moderate. The maximum level of susceptibility loss that one can have before a drug is no longer considered to be clinically effective is termed a "cutoff value". When the drug is no longer clinically effective for the particular HIV strain the virus has become resistant to that drug. For a more detailed discussion on cutoff values, see Winters et al. (2008).

The table below from the paper Junaid et al. summarizes the prediction errors for the eight NRTIs in proteochemometric model.

The model in Lapins et al. provides only RMSEP for the whole model (0.30). We did not present RMSEP for each drug separately because there were no drugs predicted exceptionally well or bad. RMSEP values for particular drugs varied from 0.26 to 0.33.

Programmatic access via Web services

See the HIVDRC Webservices page.

Invoke service from Bioclipse

See the HIVDRC plugins for Bioclipse page.